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Effexor��(venlafaxine hydrochloride)Tablets

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DESCRIPTIONEffexor (venlafaxine hydrochloride) is a structurally novel antidepressant for oral administration.It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanolhydrochloride or (±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanolhydrochloride and has the empirical formula of C17H27NO2 HCl. Its molecular weight is 313.87.The structural formula is shown below.

Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Itsoctanol:water (0.2 M sodium chloride) partition coefficient is 0.43.

Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg,75 mg, or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxides, lactose,magnesium stearate, and sodium starch glycolate.

CLINICAL PHARMACOLOGYPharmacodynamicsThe mechanism of the antidepressant action of venlafaxine in humans is believed to beassociated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies haveshown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potent

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inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopaminereuptake. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, orα-1 adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to beassociated with the various anticholinergic, sedative, and cardiovascular effects seen with otherpsychotropic drugs. Venlafaxine and ODV do not possess monoamine oxidase (MAO) inhibitoryactivity.

PharmacokineticsVenlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine(ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% ofa single dose of venlafaxine is absorbed. Approximately 87% of a venlafaxine dose is recoveredin the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%),conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination ofvenlafaxine and its metabolites is the primary route of excretion. The relative bioavailability ofvenlafaxine from a tablet was 100% when compared to an oral solution. Food has no significanteffect on the absorption of venlafaxine or on the formation of ODV.

The degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations rangingfrom 2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30% ± 12% atconcentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions withvenlafaxine are not expected.

Steady-state concentrations of both venlafaxine and ODV in plasma were attained within 3 daysof multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of75 to 450 mg total dose per day (administered on a q8h schedule). Plasma clearance, eliminationhalf-life and steady-state volume of distribution were unaltered for both venlafaxine and ODVafter multiple-dosing. Mean ± SD steady-state plasma clearance of venlafaxine and ODV is1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively; elimination half-life is 5 ± 2 and 11 ± 2 hours,respectively; and steady-state volume of distribution is 7.5 ± 3.7 L/kg and 5.7 ± 1.8 L/kg,respectively. When equal daily doses of venlafaxine were administered as either b.i.d. or t.i.d.regimens, the drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODVwere comparable following both regimens.

Age and GenderA pharmacokinetic analysis of 404 venlafaxine-treated patients from two studies involving bothb.i.d. and t.i.d. regimens showed that dose-normalized trough plasma levels of either venlafaxineor ODV were unaltered due to age or gender differences. Dosage adjustment based upon the ageor gender of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION).

Liver DiseaseIn 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine andODV was significantly altered after oral administration of venlafaxine. Venlafaxine eliminationhalf-life was prolonged by about 30%, and clearance decreased by about 50% in cirrhoticpatients compared to normal subjects. ODV elimination half-life was prolonged by about 60%and clearance decreased by about 30% in cirrhotic patients compared to normal subjects. A largedegree of intersubject variability was noted. Three patients with more severe cirrhosis had amore substantial decrease in venlafaxine clearance (about 90%) compared to normal subjects.

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Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION).

Renal DiseaseIn a renal impairment study, venlafaxine elimination half-life after oral administration wasprolonged by about 50% and clearance was reduced by about 24% in renally impaired patients(GFR = 10-70 mL/min), compared to normal subjects. In dialysis patients, venlafaxineelimination half-life was prolonged by about 180% and clearance was reduced by about 57%compared to normal subjects. Similarly, ODV elimination half-life was prolonged by about 40%although clearance was unchanged in patients with renal impairment (GFR = 10-70 mL/min)compared to normal subjects. In dialysis patients, ODV elimination half-life was prolonged byabout 142% and clearance was reduced by about 56%, compared to normal subjects. A largedegree of intersubject variability was noted.

Dosage adjustment is necessary in these patients (see DOSAGE AND ADMINISTRATION).

CLINICAL TRIALSThe efficacy of Effexor (venlafaxine hydrochloride) as a treatment for major depressive disorderwas established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials inoutpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dosetitration with Effexor in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixedEffexor doses of 75, 225, and 375 mg/day (t.i.d. schedule), and the fourth involving doses of25, 75, and 200 mg/day (b.i.d. schedule). The fifth was a 4-week study of inpatients meetingDSM-III-R criteria for major depression with melancholia whose Effexor doses were titrated in arange of 150 to 375 mg/day (t.i.d. schedule). In these 5 studies, Effexor was shown to besignificantly superior to placebo on at least 2 of the following 3 measures: Hamilton DepressionRating Scale (total score), Hamilton depressed mood item, and Clinical GlobalImpression-Severity of Illness rating. Doses from 75 to 225 mg/day were superior to placebo inoutpatient studies and a mean dose of about 350 mg/day was effective in inpatients. Data fromthe 2 fixed-dose outpatient studies were suggestive of a dose-response relationship in the rangeof 75 to 225 mg/day. There was no suggestion of increased response with doses greater than225 mg/day.

While there were no efficacy studies focusing specifically on an elderly population, elderlypatients were included among the patients studied. Overall, approximately 2/3 of all patients inthese trials were women. Exploratory analyses for age and gender effects on outcome did notsuggest any differential responsiveness on the basis of age or sex.

In one longer-term study, outpatients meeting DSM-IV criteria for major depressive disorderwho had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) wererandomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks ofobservation for relapse. Response during the open phase was defined as a CGI Severity of Illnessitem score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during thedouble-blind phase was defined as follows: (1) a reappearance of major depressive disorder asdefined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill),(2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illnessitem score of ≥4 for any patient who withdrew from the study for any reason. Patients receiving

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continued Effexor XR treatment experienced significantly lower relapse rates over thesubsequent 26 weeks compared with those receiving placebo.

In a second longer-term trial, outpatients meeting DSM-III-R criteria for major depression,recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) andcontinued to be improved [defined as the following criteria being met for days 56 through 180:(1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores >10; and (3) nosingle CGI Severity of Illness item score ≥4 (moderately ill)] during an initial 26 weeks oftreatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuationof their same Effexor dose or to placebo. The follow-up period to observe patients for relapse,defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients receivingcontinued Effexor treatment experienced significantly lower relapse rates over the subsequent52 weeks compared with those receiving placebo.

INDICATIONS AND USAGEEffexor (venlafaxine hydrochloride) is indicated for the treatment of major depressive disorder.

The efficacy of Effexor in the treatment of major depressive disorder was established in 6-weekcontrolled trials of outpatients whose diagnoses corresponded most closely to the DSM-III orDSM-III-R category of major depression and in a 4-week controlled trial of inpatients meetingdiagnostic criteria for major depression with melancholia (see CLINICAL TRIALS).

A major depressive episode implies a prominent and relatively persistent depressed or dysphoricmood that usually interferes with daily functioning (nearly every day for at least 2 weeks); itshould include at least 4 of the following 8 symptoms: change in appetite, change in sleep,psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexualdrive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impairedconcentration, and a suicide attempt or suicidal ideation.

The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeksfollowing 8 weeks of acute treatment was demonstrated in a placebo-controlled trial. Theefficacy of Effexor in maintaining an antidepressant response in patients with recurrentdepression who had responded and continued to be improved during an initial 26 weeks oftreatment and were then followed for a period of up to 52 weeks was demonstrated in a secondplacebo-controlled trial (see CLINICAL TRIALS). Nevertheless, the physician who elects touse Effexor/Effexor XR for extended periods should periodically re-evaluate the long-termusefulness of the drug for the individual patient.

CONTRAINDICATIONSHypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation.

Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated(see WARNINGS).

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WARNINGSPotential for Interaction with Monoamine Oxidase InhibitorsAdverse reactions, some of which were serious, have been reported in patients who haverecently been discontinued from a monoamine oxidase inhibitor (MAOI) and started onEffexor, or who have recently had Effexor therapy discontinued prior to initiation of anMAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting,flushing, dizziness, hyperthermia with features resembling neuroleptic malignantsyndrome, seizures, and death. In patients receiving antidepressants with pharmacologicalproperties similar to venlafaxine in combination with a monoamine oxidase inhibitor, therehave also been reports of serious, sometimes fatal, reactions. For a selective serotoninreuptake inhibitor, these reactions have included hyperthermia, rigidity, myoclonus,autonomic instability with possible rapid fluctuations of vital signs, and mental statuschanges that include extreme agitation progressing to delirium and coma. Some casespresented with features resembling neuroleptic malignant syndrome. Severe hyperthermiaand seizures, sometimes fatal, have been reported in association with the combined use oftricyclic antidepressants and MAOIs. These reactions have also been reported in patientswho have recently discontinued these drugs and have been started on an MAOI. Therefore,it is recommended that Effexor not be used in combination with an MAOI, or within atleast 14 days of discontinuing treatment with an MAOI. Based on the half-life of Effexor, atleast 7 days should be allowed after stopping Effexor before starting an MAOI.

Clinical Worsening and Suicide RiskPatients with major depressive disorder, both adult and pediatric, may experience worsening oftheir depression and/or the emergence of suicidal ideation and behavior (suicidality), whether ornot they are taking antidepressant medications, and this risk may persist until significantremission occurs. Although there has been a long-standing concern that antidepressants mayhave a role in inducing worsening of depression and the emergence of suicidality in certainpatients, a causal role for antidepressants in inducing such behaviors has not been established.Nevertheless, patients being treated with antidepressants should be observed closely forclinical worsening and suicidality, especially at the beginning of a course of drug therapy,or at the time of dose changes, either increases or decreases. Consideration should be given tochanging the therapeutic regimen, including possibly discontinuing the medication, in patientswhose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset,or was not part of the patient’s presenting symptoms.

Because of the possibility of co-morbidity between major depressive disorder and otherpsychiatric and nonpsychiatric disorders, the same precautions observed when treating patientswith major depressive disorder should be observed when treating patients with other psychiatricand nonpsychiatric disorders.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility(aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, havebeen reported in adult and pediatric patients being treated with antidepressants for majordepressive disorder as well as for other indications, both psychiatric and nonpsychiatric.Although a causal link between the emergence of such symptoms and either the worsening ofdepression and/or the emergence of suicidal impulses has not been established, considerationshould be given to changing the therapeutic regimen, including possibly discontinuing the

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medication, in patients for whom such symptoms are severe, abrupt in onset, or were not part ofthe patient’s presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressivedisorder or other indications, both psychiatric and nonpsychiatric, should be alerted aboutthe need to monitor patients for the emergence of agitation, irritability, and the othersymptoms described above, as well as the emergence of suicidality, and to report suchsymptoms immediately to health care providers. Prescriptions for Effexor should be writtenfor the smallest quantity of tablets consistent with good patient management, in order to reducethe risk of overdose.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidlyas is feasible, but with recognition that abrupt discontinuation can be associated with certainsymptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, DiscontinuingEffexor, for a description of the risks of discontinuation of Effexor).

It should be noted that Effexor is not approved for use in treating any indications in the pediatricpopulation.

A major depressive episode may be the initial presentation of bipolar disorder. It is generallybelieved (though not established in controlled trials) that treating such an episode with anantidepressant alone may increase the likelihood of precipitation of a mixed/manic episode inpatients at risk for bipolar disorder. Whether any of the symptoms described above representsuch a conversion is unknown. However, prior to initiating treatment with an antidepressant,patients should be adequately screened to determine if they are at risk for bipolar disorder; suchscreening should include a detailed psychiatric history, including a family history of suicide,bipolar disorder, and depression. It should be noted that Effexor is not approved for use intreating bipolar depression.

Sustained HypertensionVenlafaxine treatment is associated with sustained increases in blood pressure in some patients.(1) In a premarketing study comparing three fixed doses of venlafaxine(75, 225, and 375 mg/day) and placebo, a mean increase in supine diastolic blood pressure(SDBP) of 7.2 mm Hg was seen in the 375 mg/day group at week 6 compared to essentially nochanges in the 75 and 225 mg/day groups and a mean decrease in SDBP of 2.2 mm Hg in theplacebo group. (2) An analysis for patients meeting criteria for sustained hypertension (definedas treatment-emergent SDBP ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for 3 consecutivevisits) revealed a dose-dependent increase in the incidence of sustained hypertension forvenlafaxine:

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Probability of Sustained Elevation in SDBP(Pool of Premarketing Venlafaxine Studies)

Treatment Group Incidence of SustainedElevation in SDBP

Venlafaxine

< 100 mg/day 3%101-200 mg/day 5%201-300 mg/day 7%

> 300 mg/day 13%Placebo 2%

An analysis of the patients with sustained hypertension and the 19 venlafaxine patients who werediscontinued from treatment because of hypertension (<1% of total venlafaxine-treated group)revealed that most of the blood pressure increases were in a modest range(10 to 15 mm Hg, SDBP). Nevertheless, sustained increases of this magnitude could haveadverse consequences. Therefore, it is recommended that patients receiving venlafaxine haveregular monitoring of blood pressure. For patients who experience a sustained increase inblood pressure while receiving venlafaxine, either dose reduction or discontinuation should beconsidered.

PRECAUTIONSGeneralDiscontinuation of Treatment with EffexorDiscontinuation symptoms have been systematically evaluated in patients taking venlafaxine, toinclude prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospectivesurveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction ofvenlafaxine at various doses has been found to be associated with the appearance of newsymptoms, the frequency of which increased with increased dose level and with longer durationof treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, coordinationimpaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches,hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting.

During marketing of Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors),and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports ofadverse events occurring upon discontinuation of these drugs, particularly when abrupt,including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances(e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy,emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events are generallyself-limiting, there have been reports of serious discontinuation symptoms.

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Patients should be monitored for these symptoms when discontinuing treatment with Effexor. Agradual reduction in the dose rather than abrupt cessation is recommended whenever possible. Ifintolerable symptoms occur following a decrease in the dose or upon discontinuation oftreatment, then resuming the previously prescribed dose may be considered. Subsequently, thephysician may continue decreasing the dose but at a more gradual rate (see DOSAGE ANDADMINISTRATION).

Anxiety and InsomniaTreatment-emergent anxiety, nervousness, and insomnia were more commonly reported forvenlafaxine-treated patients compared to placebo-treated patients in a pooled analysis ofshort-term, double-blind, placebo-controlled depression studies:

Venlafaxine PlaceboSymptom n = 1033 n = 609

Anxiety 6% 3%Nervousness 13% 6%Insomnia 18% 10%

Anxiety, nervousness, and insomnia led to drug discontinuation in 2%, 2%, and 3%,respectively, of the patients treated with venlafaxine in the Phase 2 and Phase 3 depressionstudies.

Changes in Appetite and WeightTreatment-emergent anorexia was more commonly reported for venlafaxine-treated (11%) thanplacebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlleddepression studies. A dose-dependent weight loss was often noted in patients treated withvenlafaxine for several weeks. Significant weight loss, especially in underweight depressedpatients, may be an undesirable result of venlafaxine treatment. A loss of 5% or more of bodyweight occurred in 6% of patients treated with venlafaxine compared with 1% of patients treatedwith placebo and 3% of patients treated with another antidepressant. However, discontinuationfor weight loss associated with venlafaxine was uncommon (0.1% of venlafaxine-treated patientsin the Phase 2 and Phase 3 depression trials).

The safety and efficacy of venlafaxine therapy in combination with weight loss agents, includingphentermine, have not been established. Co-administration of Effexor and weight loss agents isnot recommended. Effexor is not indicated for weight loss alone or in combination with otherproducts.

Activation of Mania/HypomaniaDuring Phase 2 and Phase 3 trials, hypomania or mania occurred in 0.5% of patients treated withvenlafaxine. Activation of mania/hypomania has also been reported in a small proportion ofpatients with major affective disorder who were treated with other marketed antidepressants. Aswith all antidepressants, Effexor (venlafaxine hydrochloride) should be used cautiously inpatients with a history of mania.

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HyponatremiaHyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH)may occur with venlafaxine. This should be taken into consideration in patients who are, forexample, volume-depleted, elderly, or taking diuretics.

MydriasisMydriasis has been reported in association with venlafaxine; therefore patients with raisedintraocular pressure or at risk of acute narrow angle glaucoma should be monitored.

SeizuresDuring premarketing testing, seizures were reported in 0.26% (8/3082) of venlafaxine-treatedpatients. Most seizures (5 of 8) occurred in patients receiving doses of 150 mg/day or less.Effexor should be used cautiously in patients with a history of seizures. It should be discontinuedin any patient who develops seizures.

Abnormal BleedingThere have been reports of abnormal bleeding (most commonly ecchymosis) associated withvenlafaxine treatment. While a causal relationship to venlafaxine is unclear, impaired plateletaggregation may result from platelet serotonin depletion and contribute to such occurrences.

Serum Cholesterol ElevationClinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treatedpatients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlledtrials (see ADVERSE REACTIONS–Laboratory Changes). Measurement of serumcholesterol levels should be considered during long-term treatment.

Use in Patients with Concomitant IllnessClinical experience with Effexor in patients with concomitant systemic illness is limited. Cautionis advised in administering Effexor to patients with diseases or conditions that could affecthemodynamic responses or metabolism.

Effexor has not been evaluated or used to any appreciable extent in patients with a recent historyof myocardial infarction or unstable heart disease. Patients with these diagnoses weresystematically excluded from many clinical studies during the product’s premarketing testing.Evaluation of the electrocardiograms for 769 patients who received Effexor in 4- to 6-weekdouble-blind placebo-controlled trials, however, showed that the incidence of trial-emergentconduction abnormalities did not differ from that with placebo. The mean heart rate inEffexor-treated patients was increased relative to baseline by about 4 beats per minute.

The electrocardiograms for 357 patients who received Effexor XR (the extended-release form ofvenlafaxine) and 285 patients who received placebo in 8- to 12-week double-blind,placebo-controlled trials were analyzed. The mean change from baseline in corrected QT interval(QTc) for Effexor XR-treated patients was increased relative to that for placebo-treated patients(increase of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). In these same trials,the mean change from baseline in heart rate for Effexor XR-treated patients was significantlyhigher than that for placebo (a mean increase of 4 beats per minute for Effexor XR and1 beat per minute for placebo). In a flexible-dose study, with Effexor doses in the range of

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200 to 375 mg/day and mean dose greater than 300 mg/day, Effexor-treated patients had a meanincrease in heart rate of 8.5 beats per minute compared with 1.7 beats per minute in the placebogroup.

As increases in heart rate were observed, caution should be exercised in patients whoseunderlying medical conditions might be compromised by increases in heart rate (eg, patients withhyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses ofEffexor above 200 mg/day.

In patients with renal impairment (GFR=10 to 70 mL/min) or cirrhosis of the liver, theclearances of venlafaxine and its active metabolite were decreased, thus prolonging theelimination half-lives of these substances. A lower dose may be necessary (see DOSAGE ANDADMINISTRATION). Effexor (venlafaxine hydrochloride), like all antidepressants, should beused with caution in such patients.

Information for PatientsPhysicians are advised to discuss the following issues with patients for whom they prescribeEffexor:

Patients and their families should be encouraged to be alert to the emergence of anxiety,agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania,worsening of depression, and suicidal ideation, especially early during antidepressant treatment.Such symptoms should be reported to the patient’s physician, especially if they are severe, abruptin onset, or were not part of the patient’s presenting symptoms.

Interference with Cognitive and Motor PerformanceClinical studies were performed to examine the effects of venlafaxine on behavioral performanceof healthy individuals. The results revealed no clinically significant impairment of psychomotor,cognitive, or complex behavior performance. However, since any psychoactive drug may impairjudgment, thinking, or motor skills, patients should be cautioned about operating hazardousmachinery, including automobiles, until they are reasonably certain that Effexor therapy does notadversely affect their ability to engage in such activities.

PregnancyPatients should be advised to notify their physician if they become pregnant or intend to becomepregnant during therapy.

NursingPatients should be advised to notify their physician if they are breast-feeding an infant.

Concomitant MedicationPatients should be advised to inform their physicians if they are taking, or plan to take, anyprescription or over-the-counter drugs, including herbal preparations, since there is a potentialfor interactions.

AlcoholAlthough Effexor has not been shown to increase the impairment of mental and motor skillscaused by alcohol, patients should be advised to avoid alcohol while taking Effexor.

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Allergic ReactionsPatients should be advised to notify their physician if they develop a rash, hives, or a relatedallergic phenomenon.

Laboratory TestsThere are no specific laboratory tests recommended.

Drug InteractionsAs with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

AlcoholA single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODVwhen venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally,administration of venlafaxine in a stable regimen did not exaggerate the psychomotor andpsychometric effects induced by ethanol in these same subjects when they were not receivingvenlafaxine.

CimetidineConcomitant administration of cimetidine and venlafaxine in a steady-state study for both drugsresulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oralclearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximumconcentration (Cmax) of the drug were increased by about 60%. However, co-administration ofcimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in muchgreater quantity in the circulation than is venlafaxine. The overall pharmacological activity ofvenlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should benecessary for most normal adults. However, for patients with pre-existing hypertension, and forelderly patients or patients with hepatic dysfunction, the interaction associated with theconcomitant use of venlafaxine and cimetidine is not known and potentially could be morepronounced. Therefore, caution is advised with such patients.

DiazepamUnder steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg doseof diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics ofdiazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor andpsychometric effects induced by diazepam.

HaloperidolVenlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjectsdecreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, whichresulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88%when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) wasunchanged. The mechanism explaining this finding is unknown.

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LithiumThe steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affectedwhen a single 600 mg oral dose of lithium was administered to 12 healthy male subjects.O-desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on thepharmacokinetics of lithium (see also CNS-Active Drugs, below).

Drugs Highly Bound to Plasma ProteinVenlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor to apatient taking another drug that is highly protein bound should not cause increased freeconcentrations of the other drug.

Drugs that Inhibit Cytochrome P450 IsoenzymesCYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to itsactive metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the geneticpolymorphism seen in the metabolism of many antidepressants. Therefore, the potential existsfor a drug interaction between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine.However, although imipramine partially inhibited the CYP2D6-mediated metabolism ofvenlafaxine, resulting in higher plasma concentrations of venlafaxine and lower plasmaconcentrations of ODV, the total concentration of active compounds (venlafaxine plus ODV)was not affected. Additionally, in a clinical study involving CYP2D6-poor and -extensivemetabolizers, the total concentration of active compounds (venlafaxine plus ODV), was similarin the two metabolizer groups. Therefore, no dosage adjustment is required when venlafaxine iscoadministered with a CYP2D6 inhibitor.

CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor,less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically aminor pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for aclinically significant drug interaction between drugs that inhibit CYP3A4-mediated metabolismand venlafaxine is small.

The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied.Therefore, caution is advised should a patient’s therapy include venlafaxine and any agent(s) thatproduce potent simultaneous inhibition of these two enzyme systems.

Drugs Metabolized by Cytochrome P450 IsoenzymesCYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6.These findings have been confirmed in a clinical drug interaction study comparing the effect ofvenlafaxine to that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan todextrorphan.

Imipramine—Venlafaxine did not affect the pharmacokinetics of imipramine and2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in thepresence of venlafaxine. The 2-OH-desipramine AUCs increased by at least 2.5 fold (withvenlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did notaffect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated2-OH-desipramine levels is unknown.

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Risperidone—Venlafaxine administered under steady-state conditions at 150 mg/day slightlyinhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oraldose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase inrisperidone AUC. However, venlafaxine coadministration did not significantly alter thepharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone).

CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo byclinical drug interaction studies in which venlafaxine did not inhibit the metabolism of severalCYP3A4 substrates, including alprazolam, diazepam, and terfenadine.

Indinavir—In a study of 9 healthy volunteers, venlafaxine administered under steady-stateconditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose ofindinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics ofvenlafaxine and ODV. The clinical significance of this finding is unknown.

CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by aclinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, aCYP1A2 substrate.

CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouthevery 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or theCYP2C9 mediated formation of 4-hydroxy-tolbutamide.

CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam which is partiallymetabolized by CYP2C19 (see Diazepam above).

Monoamine Oxidase InhibitorsSee CONTRAINDICATIONS and WARNINGS.

CNS-Active DrugsThe risk of using venlafaxine in combination with other CNS-active drugs has not beensystematically evaluated (except in the case of those CNS-active drugs noted above).Consequently, caution is advised if the concomitant administration of venlafaxine and such drugsis required. Based on the mechanism of action of venlafaxine and the potential for serotoninsyndrome, caution is advised when venlafaxine is co-administered with other drugs that mayaffect the serotonergic neurotransmitter systems, such as triptans, serotonin reuptake inhibitors(SRIs), or lithium.

Electroconvulsive TherapyThere are no clinical data establishing the benefit of electroconvulsive therapy combined withEffexor treatment.

Postmarketing Spontaneous Drug Interaction ReportsSee ADVERSE REACTIONS, Postmarketing Reports.

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Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisVenlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day,which was 16 times, on a mg/kg basis, and 1.7 times on a mg/m2 basis, the maximumrecommended human dose. Venlafaxine was also given to rats by oral gavage for 24 months atdoses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma levels ofvenlafaxine were 1 times (male rats) and 6 times (female rats) the plasma levels of patientsreceiving the maximum recommended human dose. Plasma levels of the O-desmethyl metabolitewere lower in rats than in patients receiving the maximum recommended dose. Tumors were notincreased by venlafaxine treatment in mice or rats.

MutagenicityVenlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were notmutagenic in the Ames reverse mutation assay in Salmonella bacteria or the CHO/HGPRTmammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic in the in vitroBALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in culturedCHO cells, or the in vivo chromosomal aberration assay in rat bone marrow. ODV was notmutagenic in the in vitro CHO cell chromosomal aberration assay. There was a clastogenicresponse in the in vivo chromosomal aberration assay in rat bone marrow in male rats receiving200 times, on a mg/kg basis, or 50 times, on a mg/m2 basis, the maximum human daily dose. Theno effect dose was 67 times (mg/kg) or 17 times (mg/m2) the human dose.

Impairment of FertilityReproduction and fertility studies in rats showed no effects on male or female fertility at oraldoses of up to 8 times the maximum recommended human daily dose on a mg/kg basis, or up to2 times on a mg/m2 basis.

PregnancyTeratogenic Effects—Pregnancy Category CVenlafaxine did not cause malformations in offspring of rats or rabbits given doses up to11 times (rat) or 12 times (rabbit) the maximum recommended human daily dose ona mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human daily dose on a mg/m2 basis.However, in rats, there was a decrease in pup weight, an increase in stillborn pups, and anincrease in pup deaths during the first 5 days of lactation, when dosing began during pregnancyand continued until weaning. The cause of these deaths is not known. These effects occurred at10 times (mg/kg) or 2.5 times (mg/m2) the maximum human daily dose. The no effect dose forrat pup mortality was 1.4 times the human dose on a mg/kg basis or 0.25 times the human doseon a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women.Because animal reproduction studies are not always predictive of human response, this drugshould be used during pregnancy only if clearly needed.

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Non-teratogenic EffectsNeonates exposed to Effexor, other SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors),or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester have developedcomplications requiring prolonged hospitalization, respiratory support, and tube feeding. Suchcomplications can arise immediately upon delivery. Reported clinical findings have includedrespiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, andconstant crying. These features are consistent with either a direct toxic effect of SSRIs andSNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, theclinical picture is consistent with serotonin syndrome (see PRECAUTIONS-DrugInteractions-CNS-Active Drugs). When treating a pregnant woman with Effexor during the thirdtrimester, the physician should carefully consider the potential risks and benefits of treatment(see DOSAGE AND ADMINISTRATION).

Labor and DeliveryThe effect of Effexor® (venlafaxine hydrochloride) on labor and delivery in humans is unknown.

Nursing MothersVenlafaxine and ODV have been reported to be excreted in human milk. Because of the potentialfor serious adverse reactions in nursing infants from Effexor, a decision should be made whetherto discontinue nursing or to discontinue the drug, taking into account the importance of the drugto the mother.

Usage in ChildrenSafety and effectiveness in individuals below 18 years of age have not been established. (SeeWARNINGS-Clinical Worsening and Suicide Risk).

Geriatric UseOf the 2,897 patients in Phase 2 and Phase 3 depression studies with Effexor, 12% (357) were65 years of age or over. No overall differences in effectiveness or safety were observed betweenthese patients and younger patients, and other reported clinical experience generally has notidentified differences in response between the elderly and younger patients. However, greatersensitivity of some older individuals cannot be ruled out. As with other antidepressants, severalcases of hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH)have been reported, usually in the elderly.

The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (seeCLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on thebasis of age alone, although other clinical circumstances, some of which may be more commonin the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGEAND ADMINISTRATION).

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ADVERSE REACTIONSAssociated with Discontinuation of TreatmentNineteen percent (537/2897) of venlafaxine patients in Phase 2 and Phase 3 depression studiesdiscontinued treatment due to an adverse event. The more common events (≥ 1%) associatedwith discontinuation and considered to be drug-related (ie, those events associated with dropoutat a rate approximately twice or greater for venlafaxine compared to placebo) included:

CNS Venlafaxine Placebo

Somnolence 3% 1%Insomnia 3% 1%Dizziness 3% —Nervousness 2% —Dry mouth 2% —Anxiety 2% 1%

GastrointestinalNausea 6% 1%

UrogenitalAbnormalejaculation*

3% —

OtherHeadache 3% 1%Asthenia 2% —Sweating 2% —* Percentages based on the number of males.— Less than 1%

Incidence in Controlled TrialsCommonly Observed Adverse Events in Controlled Clinical TrialsThe most commonly observed adverse events associated with the use of Effexor (incidence of5% or greater) and not seen at an equivalent incidence among placebo-treated patients (ie,incidence for Effexor at least twice that for placebo), derived from the 1% incidence table below,were asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth,dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormalejaculation/orgasm and impotence in men.

Adverse Events Occurring at an Incidence of 1% or More Among Effexor-TreatedPatientsThe table that follows enumerates adverse events that occurred at an incidence of 1% or more,and were more frequent than in the placebo group, among Effexor-treated patients whoparticipated in short-term (4- to 8-week) placebo-controlled trials in which patients wereadministered doses in a range of 75 to 375 mg/day. This table shows the percentage of patients ineach group who had at least one episode of an event at some time during their treatment.Reported adverse events were classified using a standard COSTART-based Dictionaryterminology.

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The prescriber should be aware that these figures cannot be used to predict the incidence of sideeffects in the course of usual medical practice where patient characteristics and other factorsdiffer from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot becompared with figures obtained from other clinical investigations involving different treatments,uses and investigators. The cited figures, however, do provide the prescribing physician withsome basis for estimating the relative contribution of drug and nondrug factors to the side effectincidence rate in the population studied.

TABLE 1Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled

Clinical Trials1

Body System Preferred Term Effexor Placebo(n=1033) (n=609)

Body as a Whole Headache 25% 24%Asthenia 12% 6%Infection 6% 5%Chills 3% —Chest pain 2% 1%Trauma 2% 1%

Cardiovascular Vasodilatation 4% 3%Increased bloodpressure/hypertension 2% —Tachycardia 2% —Postural hypotension 1% —

Dermatological Sweating 12% 3%Rash 3% 2%Pruritus 1% —

Gastrointestinal Nausea 37% 11%Constipation 15% 7%Anorexia 11% 2%Diarrhea 8% 7%Vomiting 6% 2%Dyspepsia 5% 4%Flatulence 3% 2%

Metabolic Weight loss 1% —

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Body System Preferred Term Effexor Placebo(n=1033) (n=609)

Nervous System Somnolence 23% 9%Dry mouth 22% 11%Dizziness 19% 7%Insomnia 18% 10%Nervousness 13% 6%Anxiety 6% 3%Tremor 5% 1%Abnormal dreams 4% 3%Hypertonia 3% 2%Paresthesia 3% 2%Libido decreased 2% —Agitation 2% —Confusion 2% 1%Thinking abnormal 2% 1%Depersonalization 1% —Depression 1% —Urinary retention 1% —Twitching 1% —

Respiration Yawn 3% —

Special Senses Blurred vision 6% 2%Taste perversion 2% —Tinnitus 2% —Mydriasis 2% —

Urogenital System Abnormal ejaculation/orgasm 12%2 —2

Impotence 6%2 —2

Urinary frequency 3% 2%Urination impaired 2% —Orgasm disturbance 2%3 —3

1 Events reported by at least 1% of patients treated with Effexor (venlafaxine hydrochloride) are included, and arerounded to the nearest %. Events for which the Effexor incidence was equal to or less than placebo are not listedin the table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation,increased appetite, myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased,and dysmenorrhea3.

— Incidence less than 1%.2 Incidence based on number of male patients.3 Incidence based on number of female patients.

Dose Dependency of Adverse EventsA comparison of adverse event rates in a fixed-dose study comparing Effexor (venlafaxinehydrochloride) 75, 225, and 375 mg/day with placebo revealed a dose dependency for some ofthe more common adverse events associated with Effexor use, as shown in the table that follows.The rule for including events was to enumerate those that occurred at an incidence of 5% ormore for at least one of the venlafaxine groups and for which the incidence was at least twice theplacebo incidence for at least one Effexor group. Tests for potential dose relationships for theseevents (Cochran-Armitage Test, with a criterion of exact 2-sided p-value ≤ 0.05) suggested adose-dependency for several adverse events in this list, including chills, hypertension, anorexia,nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation.

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TABLE 2Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial

Effexor (mg/day)Body System/

Preferred Term Placebo 75 225 375(n=92) (n=89) (n=89) (n=88)

Body as a WholeAbdominal pain 3.3% 3.4% 2.2% 8.0%Asthenia 3.3% 16.9% 14.6% 14.8%Chills 1.1% 2.2% 5.6% 6.8%Infection 2.2% 2.2% 5.6% 2.3%

Cardiovascular SystemHypertension 1.1% 1.1% 2.2% 4.5%Vasodilatation 0.0% 4.5% 5.6% 2.3%

Digestive SystemAnorexia 2.2% 14.6% 13.5% 17.0%Dyspepsia 2.2% 6.7% 6.7% 4.5%Nausea 14.1% 32.6% 38.2% 58.0%Vomiting 1.1% 7.9% 3.4% 6.8%

Nervous SystemAgitation 0.0% 1.1% 2.2% 4.5%Anxiety 4.3% 11.2% 4.5% 2.3%Dizziness 4.3% 19.1% 22.5% 23.9%Insomnia 9.8% 22.5% 20.2% 13.6%Libido decreased 1.1% 2.2% 1.1% 5.7%Nervousness 4.3% 21.3% 13.5% 12.5%Somnolence 4.3% 16.9% 18.0% 26.1%Tremor 0.0% 1.1% 2.2% 10.2%

Respiratory SystemYawn 0.0% 4.5% 5.6% 8.0%

Skin and AppendagesSweating 5.4% 6.7% 12.4% 19.3%

Special SensesAbnormality ofaccommodation 0.0% 9.1% 7.9% 5.6%

Urogenital SystemAbnormalejaculation/orgasm 0.0% 4.5% 2.2% 12.5%Impotence 0.0% 5.8% 2.1% 3.6%(Number of men) (n=63) (n=52) (n=48) (n=56)

Adaptation to Certain Adverse EventsOver a 6-week period, there was evidence of adaptation to some adverse events with continued therapy(eg, dizziness and nausea), but less to other effects (eg, abnormal ejaculation and dry mouth).

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Vital Sign ChangesEffexor (venlafaxine hydrochloride) treatment (averaged over all dose groups) in clinical trialswas associated with a mean increase in pulse rate of approximately 3 beats per minute, comparedto no change for placebo. In a flexible-dose study, with doses in the range of 200 to 375 mg/dayand mean dose greater than 300 mg/day, the mean pulse was increased by about 2 beats perminute compared with a decrease of about 1 beat per minute for placebo.

In controlled clinical trials, Effexor was associated with mean increases in diastolic bloodpressure ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to meandecreases ranging from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency forblood pressure increase (see WARNINGS).

Laboratory ChangesOf the serum chemistry and hematology parameters monitored during clinical trials with Effexor,a statistically significant difference with placebo was seen only for serum cholesterol. Inpremarketing trials, treatment with Effexor tablets was associated with a mean final on-therapyincrease in total cholesterol of 3 mg/dL.

Patients treated with Effexor tablets for at least 3 months in placebo-controlled 12-monthextension trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL comparedwith a decrease of 7.1 mg/dL among placebo-treated patients. This increase was durationdependent over the study period and tended to be greater with higher doses. Clinically relevantincreases in serum cholesterol, defined as 1) a final on-therapy increase in serum cholesterol≥50 mg/dL from baseline and to a value ≥261 mg/dL or 2) an average on-therapy increase inserum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL, were recorded in 5.3%of venlafaxine-treated patients and 0.0% of placebo-treated patients (seePRECAUTIONS-General-Serum Cholesterol Elevation).

ECG ChangesIn an analysis of ECGs obtained in 769 patients treated with Effexor and 450 patients treatedwith placebo in controlled clinical trials, the only statistically significant difference observed wasfor heart rate, ie, a mean increase from baseline of 4 beats per minute for Effexor. In aflexible-dose study, with doses in the range of 200 to 375 mg/day and mean dose greater than300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with1.7 beats per minute for placebo (see PRECAUTIONS, General, Use in Patients withConcomitant Illness).

Other Events Observed During the Premarketing Evaluation of VenlafaxineDuring its premarketing assessment, multiple doses of Effexor were administered to 2897patients in Phase 2 and Phase 3 studies. In addition, in premarketing assessment of Effexor XR(the extended release form of venlafaxine), multiple doses were administered to 705 patients inPhase 3 major depressive disorder studies and Effexor was administered to 96 patients. Duringits premarketing assessment for Generalized Anxiety Disorder, multiple doses of Effexor XRwere administered to 476 patients in Phase 3 studies. The conditions and duration of exposure tovenlafaxine in both development programs varied greatly, and included (in overlappingcategories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexoronly) and outpatient studies, fixed-dose and titration studies. Untoward events associated with

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this exposure were recorded by clinical investigators using terminology of their own choosing.Consequently, it is not possible to provide a meaningful estimate of the proportion of individualsexperiencing adverse events without first grouping similar types of untoward events into asmaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a standardCOSTART-based Dictionary terminology. The frequencies presented, therefore, represent theproportion of the 4174 patients exposed to multiple doses of either formulation of venlafaxinewho experienced an event of the type cited on at least one occasion while receiving venlafaxine.All reported events are included except those already listed in Table 1 and those events for whicha drug cause was remote. If the COSTART term for an event was so general as to beuninformative, it was replaced with a more informative term. It is important to emphasize that,although the events reported occurred during treatment with venlafaxine, they were notnecessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency usingthe following definitions: frequent adverse events are defined as those occurring on one or moreoccasions in at least 1/100 patients; infrequent adverse events are those occurring in1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Body as a whole—Frequent: chest pain substernal, neck pain; Infrequent: face edema,intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction,suicide attempt; Rare: appendicitis, bacteremia, carcinoma, cellulitis, withdrawal syndrome.

Cardiovascular system—Frequent: migraine; Infrequent: angina pectoris, arrhythmia,extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands),syncope, thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block,bigeminy, bradycardia, bundle branch block, capillary fragility, cerebral ischemia, coronaryartery disease, congestive heart failure, heart arrest, mitral valve disorder, mucocutaneoushemorrhage, myocardial infarct, pallor.

Digestive system—Frequent: eructation; Infrequent: bruxism, colitis, dysphagia, tongueedema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectalhemorrhage, hemorrhoids, melena, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis,cholelithiasis, hematemesis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis,jaundice, intestinal obstruction, oral moniliasis, proctitis, increased salivation, soft stools, tonguediscoloration.

Endocrine system—Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis.

Hemic and lymphatic system—Frequent: ecchymosis; Infrequent: anemia, leukocytosis,leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleedingtime increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura.

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Metabolic and nutritional—Frequent: edema, weight gain; Infrequent: alkaline phosphataseincreased, glycosuria, hypercholesteremia, hyperglycemia, hyperuricemia, hypoglycemia,hypokalemia, SGOT increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased,creatinine increased, diabetes mellitus, dehydration, gout, healing abnormal, hemochromatosis,hypercalcinuria, hyperkalemia, hyperlipemia, hyperphosphatemia, hyponatremia,hypophosphatemia, hypoproteinemia, SGPT increased, uremia.

Musculoskeletal system—Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, legcramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis,osteosclerosis, rheumatoid arthritis, tendon rupture.

Nervous system—Frequent: emotional lability, trismus, vertigo; Infrequent: apathy, ataxia,circumoral paresthesia, CNS stimulation, euphoria, hallucinations, hostility, hyperesthesia,hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia,neuropathy, paranoid reaction, psychosis, seizure, abnormal speech, stupor; Rare: akathisia,akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular accident,loss of consciousness, delusions, dementia, dystonia, facial paralysis, abnormal gait,Guillain-Barre Syndrome, hypokinesia, neuritis, nystagmus, paresis, psychotic depression,reflexes decreased, reflexes increased, suicidal ideation, torticollis.

Respiratory system—Frequent: bronchitis, dyspnea; Infrequent: asthma, chest congestion,epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare:atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus,sleep apnea.

Skin and appendages—Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin,eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum,exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis,hirsutism, leukoderma, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae.

Special senses—Frequent: abnormality of accommodation, abnormal vision; Infrequent:cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, exophthalmos, eye pain, hyperacusis,otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis,chromatopsia, conjunctival edema, deafness, glaucoma, retinal hemorrhage, subconjunctivalhemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitisexterna, scleritis, uveitis.

Urogenital system—Frequent: metrorrhagia*, prostatitis*, vaginitis*; Infrequent: albuminuria,amenorrhea*, cystitis, dysuria, hematuria, female lactation*, leukorrhea*, menorrhagia*,nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary urgency,vaginal hemorrhage*; Rare: abortion*, anuria, breast discharge, breast engorgement, breastenlargement, endometriosis*, fibrocystic breast, calcium crystalluria, cervicitis*, ovarian cyst*,prolonged erection*, gynecomastia (male)*, hypomenorrhea*, kidney calculus, kidney pain,kidney function abnormal, mastitis, menopause*, pyelonephritis, oliguria, salpingitis*,urolithiasis, uterine hemorrhage*, uterine spasm.*

* Based on the number of men and women as appropriate.

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Postmarketing ReportsVoluntary reports of other adverse events temporally associated with the use of venlafaxine thathave been received since market introduction and that may have no causal relationship with theuse of venlafaxine include the following: agranulocytosis, anaphylaxis, aplastic anemia,catatonia, congenital anomalies, CPK increased, deep vein thrombophlebitis, delirium,EKG abnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation,supraventricular tachycardia, ventricular extrasystole, and rare reports of ventricular fibrillationand ventricular tachycardia, including torsade de pointes; epidermal necrosis/Stevens-JohnsonSyndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardivedyskinesia), hemorrhage (including eye and gastrointestinal bleeding), hepatic events (includingGGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, orfailure; and fatty liver), involuntary movements, LDH increased, neuroleptic malignantsyndrome-like events (including a case of a 10-year-old who may have been takingmethylphenidate, was treated and recovered), neutropenia, night sweats, pancreatitis,pancytopenia, panic, prolactin increased, pulmonary eosinophilia, renal failure, rhabdomyolysis,serotonin syndrome, shock-like electrical sensations or tinnitus (in some cases, subsequent to thediscontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretichormone secretion (usually in the elderly).

There have been reports of elevated clozapine levels that were temporally associated withadverse events, including seizures, following the addition of venlafaxine. There have beenreports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxinewas given to patients receiving warfarin therapy.

DRUG ABUSE AND DEPENDENCEControlled Substance ClassEffexor (venlafaxine hydrochloride) is not a controlled substance.

Physical and Psychological DependenceIn vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine,phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors.

Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primatedrug discrimination studies, venlafaxine showed no significant stimulant or depressant abuseliability.

Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGEAND ADMINISTRATION).

While Effexor has not been systematically studied in clinical trials for its potential for abuse,there was no indication of drug-seeking behavior in the clinical trials. However, it is not possibleto predict on the basis of premarketing experience the extent to which a CNS active drug will bemisused, diverted, and/or abused once marketed. Consequently, physicians should carefullyevaluate patients for history of drug abuse and follow such patients closely, observing them forsigns of misuse or abuse of Effexor (eg, development of tolerance, incrementation of dose,drug-seeking behavior).

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OVERDOSAGEHuman ExperienceThere were 14 reports of acute overdose with Effexor (venlafaxine hydrochloride), either aloneor in combination with other drugs and/or alcohol, among the patients included in thepremarketing evaluation. The majority of the reports involved ingestions in which the total doseof Effexor taken was estimated to be no more than several-fold higher than the usual therapeuticdose. The 3 patients who took the highest doses were estimated to have ingested approximately6.75 g, 2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patientswere 6.24 and 2.35 µg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxinewere 3.37 and 1.30 µg/mL, respectively. Plasma venlafaxine levels were not obtained for thepatient who ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Mostpatients reported no symptoms. Among the remaining patients, somnolence was the mostcommonly reported symptom. The patient who ingested 2.75 g of venlafaxine was observed tohave 2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msecat baseline. Mild sinus tachycardia was reported in 2 of the other patients.

In postmarketing experience, overdose with venlafaxine has occurred predominantly incombination with alcohol and/or other drugs. Electrocardiogram changes (eg, prolongation ofQT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia,bradycardia, hypotension, altered level of consciousness (ranging from somnolence to coma),rhabdomyolysis, seizures, vertigo, and death have been reported.

Management of OverdosageTreatment should consist of those general measures employed in the management of overdosagewith any antidepressant.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs.General supportive and symptomatic measures are also recommended. Induction of emesis is notrecommended. Gastric lavage with a large-bore orogastric tube with appropriate airwayprotection, if needed, may be indicated if performed soon after ingestion or in symptomaticpatients. Activated charcoal should be administered. Due to the large volume of distribution ofthis drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be ofbenefit. No specific antidotes for venlafaxine are known.

In managing overdosage, consider the possibility of multiple drug involvement. The physicianshould consider contacting a poison control center for additional information on the treatment ofany overdose. Telephone numbers for certified poison control centers are listed in thePhysicians’ Desk Reference (PDR).

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DOSAGE AND ADMINISTRATIONInitial TreatmentThe recommended starting dose for Effexor is 75 mg/day, administered in two or three divideddoses, taken with food. Depending on tolerability and the need for further clinical effect, the dosemay be increased to 150 mg/day. If needed, the dose should be further increased up to225 mg/day. When increasing the dose, increments of up to 75 mg/day should be made atintervals of no less than 4 days. In outpatient settings there was no evidence of usefulness ofdoses greater than 225 mg/day for moderately depressed patients, but more severely depressedinpatients responded to a mean dose of 350 mg/day. Certain patients, including more severelydepressed patients, may therefore respond more to higher doses, up to a maximum of375 mg/day, generally in three divided doses (see PRECAUTIONS, General, Use in Patientswith Concomitant Illness).

Special PopulationsTreatment of Pregnant Women During the Third TrimesterNeonates exposed to Effexor, other SNRIs, or SSRIs, late in the third trimester have developedcomplications requiring prolonged hospitalization, respiratory support, and tube feeding (seePRECAUTIONS). When treating pregnant women with Effexor during the third trimester, thephysician should carefully consider the potential risks and benefits of treatment. The physicianmay consider tapering Effexor in the third trimester.

Dosage for Patients with Hepatic ImpairmentGiven the decrease in clearance and increase in elimination half-life for both venlafaxine andODV that is observed in patients with hepatic cirrhosis compared to normal subjects (seeCLINICAL PHARMACOLOGY), it is recommended that the total daily dose be reduced by50% in patients with moderate hepatic impairment. Since there was much individual variabilityin clearance between patients with cirrhosis, it may be necessary to reduce the dose even morethan 50%, and individualization of dosing may be desirable in some patients.

Dosage for Patients with Renal ImpairmentGiven the decrease in clearance for venlafaxine and the increase in elimination half-life for bothvenlafaxine and ODV that is observed in patients with renal impairment(GFR = 10 to 70 mL/min) compared to normals (see CLINICAL PHARMACOLOGY), it isrecommended that the total daily dose be reduced by 25% in patients with mild to moderate renalimpairment. It is recommended that the total daily dose be reduced by 50% and the dose bewithheld until the dialysis treatment is completed (4 hrs) in patients undergoing hemodialysis.Since there was much individual variability in clearance between patients with renal impairment,individualization of dosing may be desirable in some patients.

Dosage for Elderly PatientsNo dose adjustment is recommended for elderly patients on the basis of age. As with anyantidepressant, however, caution should be exercised in treating the elderly. Whenindividualizing the dosage, extra care should be taken when increasing the dose.

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Maintenance TreatmentIt is generally agreed that acute episodes of major depressive disorder require several months orlonger of sustained pharmacological therapy beyond response to the acute episode. In one study,in which patients responding during 8 weeks of acute treatment with Effexor XR were assignedrandomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during26 weeks of maintenance treatment as they had received during the acute stabilization phase,longer-term efficacy was demonstrated. A second longer-term study has demonstrated theefficacy of Effexor in maintaining an antidepressant response in patients with recurrentdepression who had responded and continued to be improved during an initial 26 weeks oftreatment and were then randomly assigned to placebo or Effexor for periods of up to 52 weekson the same dose (100 to 200 mg/day, on a b.i.d. schedule) (see CLINICAL TRIALS). Basedon these limited data, it is not known whether or not the dose of Effexor/Effexor XR needed formaintenance treatment is identical to the dose needed to achieve an initial response. Patientsshould be periodically reassessed to determine the need for maintenance treatment and theappropriate dose for such treatment.

Discontinuing Effexor (venlafaxine hydrochloride)Symptoms associated with discontinuation of Effexor, other SNRIs, and SSRIs, have beenreported (see PRECAUTIONS). Patients should be monitored for these symptoms whendiscontinuing treatment. A gradual reduction in the dose rather than abrupt cessation isrecommended whenever possible. If intolerable symptoms occur following a decrease in the doseor upon discontinuation of treatment, then resuming the previously prescribed dose may beconsidered. Subsequently, the physician may continue decreasing the dose but at a more gradualrate.

SWITCHING PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITORAt least 14 days should elapse between discontinuation of an MAOI and initiation of therapywith Effexor. In addition, at least 7 days should be allowed after stopping Effexor before startingan MAOI (see CONTRAINDICATIONS and WARNINGS).

HOW SUPPLIEDEffexor� (venlafaxine hydrochloride) Tablets are available as follows:25 mg, peach, shield-shaped tablet with “25” and a “ ” on one side and “701” on scoredreverse side.

NDC 0008-0701-01, bottle of 100 tablets.NDC 0008-0701-02, carton of 10 Redipak blister strips of 10 tablets each.

37.5 mg, peach, shield-shaped tablet with “37.5” and a “ ”on one side and “781” on scoredreverse side.


50 mg, peach, shield-shaped tablet with “50” and a “ ” on one side and “703” on scoredreverse side.


27





The appearance of these tablets is a trademark of Wyeth Pharmaceuticals.

Store at controlled room temperature 20º to 25ºC (68º to 77ºF) in a dry place.

Dispense in a well-closed container as defined in the USP.

Wyeth Pharmaceuticals Inc.Philadelphia, PA 19101

W10402C007ET01

Rev 04/04

1

Effexor�� XR(venlafaxine hydrochloride)Extended-Release Capsules

�� only

This product’s label may have been revised after this insert was usedin production. For further product information and current packageinsert, please visit www.wyeth.com or call our medicalcommunications department toll-free at 1-800-934-5556.

DESCRIPTIONEffexor XR is an extended-release capsule for oral administration that contains venlafaxinehydrochloride, a structurally novel antidepressant. It is designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[α- [(dimethylamino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2

hydrochloride. Its molecular weight is 313.87. The structural formula is shown below.

Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of572 mg/mL in water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water(0.2 M sodium chloride) partition coefficient is 0.43.

Effexor XR is formulated as an extended-release capsule for once-a-day oral administration.Drug release is controlled by diffusion through the coating membrane on the spheroids and is notpH dependent. Capsules contain venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg, or150 mg venlafaxine. Inactive ingredients consist of cellulose, ethylcellulose, gelatin,hypromellose, iron oxide, and titanium dioxide.

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CLINICAL PHARMACOLOGYPharmacodynamicsThe mechanism of the antidepressant action of venlafaxine in humans is believed to beassociated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies haveshown that venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), are potentinhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopaminereuptake. Venlafaxine and ODV have no significant affinity for muscarinic cholinergic,H1-histaminergic, or α1-adrenergic receptors in vitro. Pharmacologic activity at these receptors ishypothesized to be associated with the various anticholinergic, sedative, and cardiovasculareffects seen with other psychotropic drugs. Venlafaxine and ODV do not possess monoamineoxidase (MAO) inhibitory activity.

PharmacokineticsSteady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oralmultiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of75 to 450 mg/day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is1.3±0.6 and 0.4±0.2 L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours,respectively; and apparent (steady-state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg,respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasmaproteins (27% and 30%, respectively).

AbsorptionVenlafaxine is well absorbed and extensively metabolized in the liver. O-desmethylvenlafaxine(ODV) is the only major active metabolite. On the basis of mass balance studies, at least 92% ofa single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about45%.

Administration of Effexor XR (150 mg q24 hours) generally resulted in lower Cmax (150 ng/mLfor venlafaxine and 260 ng/mL for ODV) and later Tmax (5.5 hours for venlafaxine and 9 hoursfor ODV) than for immediate release venlafaxine tablets (Cmax’s for immediate release 75 mgq12 hours were 225 ng/mL for venlafaxine and 290 ng/mL for ODV; Tmax’s were 2 hours forvenlafaxine and 3 hours for ODV). When equal daily doses of venlafaxine were administered aseither an immediate release tablet or the extended-release capsule, the exposure to bothvenlafaxine and ODV was similar for the two treatments, and the fluctuation in plasmaconcentrations was slightly lower with the Effexor XR capsule. Effexor XR, therefore, providesa slower rate of absorption, but the same extent of absorption compared with the immediaterelease tablet.

Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time ofadministration (AM vs PM) did not affect the pharmacokinetics of venlafaxine and ODV fromthe 75 mg Effexor XR capsule.

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Metabolism and ExcretionFollowing absorption, venlafaxine undergoes extensive presystemic metabolism in the liver,primarily to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and otherminor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6;this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (“poormetabolizers”) had increased levels of venlafaxine and reduced levels of ODV compared topeople with normal CYP2D6 (“extensive metabolizers”). The differences between the CYP2D6poor and extensive metabolizers, however, are not expected to be clinically important becausethe sum of venlafaxine and ODV is similar in the two groups and venlafaxine and ODV arepharmacologically approximately equiactive and equipotent.

Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours asunchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minorinactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus theprimary route of excretion.

Special PopulationsAge and Gender: A population pharmacokinetic analysis of 404 venlafaxine-treated patientsfrom two studies involving both b.i.d. and t.i.d. regimens showed that dose-normalized troughplasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosageadjustment based on the age or gender of a patient is generally not necessary (see DOSAGEAND ADMINISTRATION).

Extensive/Poor Metabolizers: Plasma concentrations of venlafaxine were higher in CYP2D6poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxineand ODV was similar in poor and extensive metabolizer groups, however, there is no need fordifferent venlafaxine dosing regimens for these two groups.

Liver Disease: In 9 patients with hepatic cirrhosis, the pharmacokinetic disposition of bothvenlafaxine and ODV was significantly altered after oral administration of venlafaxine.Venlafaxine elimination half-life was prolonged by about 30%, and clearance decreased by about50% in cirrhotic patients compared to normal subjects. ODV elimination half-life was prolongedby about 60%, and clearance decreased by about 30% in cirrhotic patients compared to normalsubjects. A large degree of intersubject variability was noted. Three patients with more severecirrhosis had a more substantial decrease in venlafaxine clearance (about 90%) compared tonormal subjects. Dosage adjustment is necessary in these patients (see DOSAGE ANDADMINISTRATION).

Renal Disease: In a renal impairment study, venlafaxine elimination half-life after oraladministration was prolonged by about 50% and clearance was reduced by about 24% in renallyimpaired patients (GFR=10 to 70 mL/min), compared to normal subjects. In dialysis patients,venlafaxine elimination half-life was prolonged by about 180% and clearance was reduced byabout 57% compared to normal subjects. Similarly, ODV elimination half-life was prolonged byabout 40% although clearance was unchanged in patients with renal impairment(GFR=10 to 70 mL/min) compared to normal subjects. In dialysis patients, ODV eliminationhalf-life was prolonged by about 142% and clearance was reduced by about 56% compared to

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normal subjects. A large degree of intersubject variability was noted. Dosage adjustment isnecessary in these patients (see DOSAGE AND ADMINISTRATION).

Clinical TrialsMajor Depressive DisorderThe efficacy of Effexor XR (venlafaxine hydrochloride) extended-release capsules as a treatmentfor major depressive disorder was established in two placebo-controlled, short-term,flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for majordepressive disorder.

A 12-week study utilizing Effexor XR doses in a range 75 to 150 mg/day (mean dose forcompleters was 136 mg/day) and an 8-week study utilizing Effexor XR doses in a range75 to 225 mg/day (mean dose for completers was 177 mg/day) both demonstrated superiority ofEffexor XR over placebo on the HAM-D total score, HAM-D Depressed Mood Item, theMADRS total score, the Clinical Global Impressions (CGI) Severity of Illness item, and theCGI Global Improvement item. In both studies, Effexor XR was also significantly better thanplacebo for certain factors of the HAM-D, including the anxiety/somatization factor, thecognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety score.

A 4-week study of inpatients meeting DSM-III-R criteria for major depressive disorder withmelancholia utilizing Effexor (the immediate release form of venlafaxine) in a range of150 to 375 mg/day (t.i.d. schedule) demonstrated superiority of Effexor over placebo. The meandose in completers was 350 mg/day.

Examination of gender subsets of the population studied did not reveal any differentialresponsiveness on the basis of gender.

In one longer-term study, outpatients meeting DSM-IV criteria for major depressive disorderwho had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) wererandomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks ofobservation for relapse. Response during the open phase was defined as a CGI Severity of Illnessitem score of ≤3 and a HAM-D-21 total score of ≤10 at the day 56 evaluation. Relapse during thedouble-blind phase was defined as follows: (1) a reappearance of major depressive disorder asdefined by DSM-IV criteria and a CGI Severity of Illness item score of ≥4 (moderately ill),(2) 2 consecutive CGI Severity of Illness item scores of ≥4, or (3) a final CGI Severity of Illnessitem score of ≥4 for any patient who withdrew from the study for any reason. Patients receivingcontinued Effexor XR treatment experienced significantly lower relapse rates over thesubsequent 26 weeks compared with those receiving placebo.

In a second longer-term trial, outpatients meeting DSM-III-R criteria for major depressivedisorder, recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56evaluation) and continued to be improved [defined as the following criteria being met for days56 through 180: (1) no HAM-D-21 total score ≥20; (2) no more than 2 HAM-D-21 total scores>10, and (3) no single CGI Severity of Illness item score ≥4(moderately ill)] during an initial26 weeks of treatment on Effexor (100 to 200 mg/day, on a b.i.d. schedule) were randomized tocontinuation of their same Effexor dose or to placebo. The follow-up period to observe patientsfor relapse, defined as a CGI Severity of Illness item score ≥4, was for up to 52 weeks. Patients

5

receiving continued Effexor treatment experienced significantly lower relapse rates over thesubsequent 52 weeks compared with those receiving placebo.

Generalized Anxiety DisorderThe efficacy of Effexor XR capsules as a treatment for Generalized Anxiety Disorder (GAD)was established in two 8-week, placebo-controlled, fixed-dose studies, one 6-month,placebo-controlled, fixed-dose study, and one 6-month, placebo-controlled, flexible-dose studyin outpatients meeting DSM-IV criteria for GAD.

One 8-week study evaluating Effexor XR doses of 75, 150, and 225 mg/day, and placebo showedthat the 225 mg/day dose was more effective than placebo on the Hamilton Rating Scale forAnxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the ClinicalGlobal Impressions (CGI) scale. While there was also evidence for superiority over placebo forthe 75 and 150 mg/day doses, these doses were not as consistently effective as the highest dose.A second 8-week study evaluating Effexor XR doses of 75 and 150 mg/day and placebo showedthat both doses were more effective than placebo on some of these same outcomes; however, the75 mg/day dose was more consistently effective than the 150 mg/day dose. A dose-responserelationship for effectiveness in GAD was not clearly established in the 75 to 225 mg/day doserange utilized in these two studies.

Two 6-month studies, one evaluating Effexor XR doses of 37.5, 75, and 150 mg/day and theother evaluating Effexor XR doses of 75 to 225 mg/day, showed that daily doses of 75 mg orhigher were more effective than placebo on the HAM-A total, both the HAM-A anxiety andtension items, and the CGI scale during 6 months of treatment. While there was also evidence forsuperiority over placebo for the 37.5 mg/day dose, this dose was not as consistently effective asthe higher doses.

Examination of gender subsets of the population studied did not reveal any differentialresponsiveness on the basis of gender.

Social Anxiety Disorder (Social Phobia)The efficacy of Effexor XR capsules as a treatment for Social Anxiety Disorder (also known asSocial Phobia) was established in two double-blind, parallel group, 12-week, multicenter,placebo-controlled, flexible-dose studies in adult outpatients meeting DSM-IV criteria forSocial Anxiety Disorder. Patients received doses in a range of 75 to 225 mg/day. Efficacy wasassessed with the Liebowitz Social Anxiety Scale (LSAS). In these two trials, Effexor XR wassignificantly more effective than placebo on change from baseline to endpoint on the LSAS totalscore.

Examination of subsets of the population studied did not reveal any differential responsivenesson the basis of gender. There was insufficient information to determine the effect of age or raceon outcome in these studies.

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INDICATIONS AND USAGEMajor Depressive DisorderEffexor XR (venlafaxine hydrochloride) extended-release capsules is indicated for the treatmentof major depressive disorder.

The efficacy of Effexor XR in the treatment of major depressive disorder was established in8- and 12-week controlled trials of outpatients whose diagnoses corresponded most closely to theDSM-III-R or DSM-IV category of major depressive disorder (see Clinical Trials).

A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearlyevery day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly allactivities, representing a change from previous functioning, and includes the presence of at leastfive of the following nine symptoms during the same two-week period: depressed mood,markedly diminished interest or pleasure in usual activities, significant change in weight and/orappetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue,feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attemptor suicidal ideation.

The efficacy of Effexor (the immediate release form of venlafaxine) in the treatment of majordepressive disorder in inpatients meeting diagnostic criteria for major depressive disorder withmelancholia was established in a 4-week controlled trial (see Clinical Trials). The safety andefficacy of Effexor XR in hospitalized depressed patients have not been adequately studied.

The efficacy of Effexor XR in maintaining a response in major depressive disorder for up to26 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial.The efficacy of Effexor in maintaining a response in patients with recurrent major depressivedisorder who had responded and continued to be improved during an initial 26 weeks oftreatment and were then followed for a period of up to 52 weeks was demonstrated in a secondplacebo-controlled trial (see Clinical Trials). Nevertheless, the physician who elects to useEffexor/Effexor XR for extended periods should periodically re-evaluate the long-termusefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Generalized Anxiety DisorderEffexor XR is indicated for the treatment of Generalized Anxiety Disorder (GAD) as defined inDSM-IV. Anxiety or tension associated with the stress of everyday life usually does not requiretreatment with an anxiolytic.

The efficacy of Effexor XR in the treatment of GAD was established in 8-week and 6-monthplacebo-controlled trials in outpatients diagnosed with GAD according to DSM-IV criteria (seeClinical Trials).

Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry(apprehensive expectation) that is persistent for at least 6 months and which the person findsdifficult to control. It must be associated with at least 3 of the following 6 symptoms:restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating ormind going blank, irritability, muscle tension, sleep disturbance.

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Although the effectiveness of Effexor XR has been demonstrated in 6-month clinical trials inpatients with GAD, the physician who elects to use Effexor XR for extended periods shouldperiodically re-evaluate the long-term usefulness of the drug for the individual patient (seeDOSAGE AND ADMINISTRATION).

Social Anxiety DisorderEffexor XR is indicated for the treatment of Social Anxiety Disorder, also known as SocialPhobia, as defined in DSM-IV (300.23).

Social Anxiety Disorder (DSM-IV) is characterized by a marked and persistent fear of 1 or moresocial or performance situations in which the person is exposed to unfamiliar people or topossible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety,which may approach the intensity of a panic attack. The feared situations are avoided or enduredwith intense anxiety or distress. The avoidance, anxious anticipation, or distress in the fearedsituation(s) interferes significantly with the person's normal routine, occupational or academicfunctioning, or social activities or relationships, or there is a marked distress about having thephobias. Lesser degrees of performance anxiety or shyness generally do not requirepsychopharmacological treatment.

The efficacy of Effexor XR in the treatment of Social Anxiety Disorder was established in two12-week placebo-controlled trials in adult outpatients with Social Anxiety Disorder (DSM-IV).Effexor XR has not been studied in children or adolescents with Social Anxiety Disorder (seeClinical Trials).

The effectiveness of Effexor XR in the long-term treatment of Social Anxiety Disorder, ie, formore than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials.Therefore, the physician who elects to use Effexor XR for extended periods should periodicallyre-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE ANDADMINISTRATION).

CONTRAINDICATIONSHypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation.

Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated(see WARNINGS).

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WARNINGSPotential for Interaction with Monoamine Oxidase InhibitorsAdverse reactions, some of which were serious, have been reported in patients who haverecently been discontinued from a monoamine oxidase inhibitor (MAOI) and started onvenlafaxine, or who have recently had venlafaxine therapy discontinued prior to initiationof an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea,vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignantsyndrome, seizures, and death. In patients receiving antidepressants with pharmacologicalproperties similar to venlafaxine in combination with an MAOI, there have also beenreports of serious, sometimes fatal, reactions. For a selective serotonin reuptake inhibitor,these reactions have included hyperthermia, rigidity, myoclonus, autonomic instability withpossible rapid fluctuations of vital signs, and mental status changes that include extremeagitation progressing to delirium and coma. Some cases presented with features resemblingneuroleptic malignant syndrome. Severe hyperthermia and seizures, sometimes fatal, havebeen reported in association with the combined use of tricyclic antidepressants andMAOIs. These reactions have also been reported in patients who have recentlydiscontinued these drugs and have been started on an MAOI. The effects of combined useof venlafaxine and MAOIs have not been evaluated in humans or animals. Therefore,because venlafaxine is an inhibitor of both norepinephrine and serotonin reuptake, it isrecommended that Effexor XR (venlafaxine hydrochloride) extended-release capsules notbe used in combination with an MAOI, or within at least 14 days of discontinuingtreatment with an MAOI. Based on the half-life of venlafaxine, at least 7 days should beallowed after stopping venlafaxine before starting an MAOI.

Clinical Worsening and Suicide RiskPatients with major depressive disorder, both adult and pediatric, may experience worsening oftheir depression and/or the emergence of suicidal ideation and behavior (suicidality), whether ornot they are taking antidepressant medications, and this risk may persist until significantremission occurs. Although there has been a long-standing concern that antidepressants mayhave a role in inducing worsening of depression and the emergence of suicidality in certainpatients, a causal role for antidepressants in inducing such behaviors has not been established.Nevertheless, patients being treated with antidepressants should be observed closely forclinical worsening and suicidality, especially at the beginning of a course of drug therapy,or at the time of dose changes, either increases or decreases. Consideration should be given tochanging the therapeutic regimen, including possibly discontinuing the medication, in patientswhose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset,or was not part of the patient’s presenting symptoms.

Because of the possibility of co-morbidity between major depressive disorder and otherpsychiatric and nonpsychiatric disorders, the same precautions observed when treating patientswith major depressive disorder should be observed when treating patients with other psychiatricand nonpsychiatric disorders.

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The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility(aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, havebeen reported in adult and pediatric patients being treated with antidepressants for majordepressive disorder as well as for other indications, both psychiatric and nonpsychiatric.Although a causal link between the emergence of such symptoms and either the worsening ofdepression and/or the emergence of suicidal impulses has not been established, considerationshould be given to changing the therapeutic regimen, including possibly discontinuing themedication, in patients for whom such symptoms are severe, abrupt in onset, or were not part ofthe patient’s presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressivedisorder or other indications, both psychiatric and nonpsychiatric, should be alerted aboutthe need to monitor patients for the emergence of agitation, irritability, and the othersymptoms described above, as well as the emergence of suicidality, and to report suchsymptoms immediately to health care providers. Prescriptions for Effexor XR should bewritten for the smallest quantity of capsules consistent with good patient management, in orderto reduce the risk of overdose.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidlyas is feasible, but with recognition that abrupt discontinuation can be associated with certainsymptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, DiscontinuingEffexor XR, for a description of the risks of discontinuation of Effexor XR).

It should be noted that Effexor XR is not approved for use in treating any indications in thepediatric population.

A major depressive episode may be the initial presentation of bipolar disorder. It is generallybelieved (though not established in controlled trials) that treating such an episode with anantidepressant alone may increase the likelihood of precipitation of a mixed/manic episode inpatients at risk for bipolar disorder. Whether any of the symptoms described above representsuch a conversion is unknown. However, prior to initiating treatment with an antidepressant,patients should be adequately screened to determine if they are at risk for bipolar disorder; suchscreening should include a detailed psychiatric history, including a family history of suicide,bipolar disorder, and depression. It should be noted that Effexor XR is not approved for use intreating bipolar depression.

Sustained HypertensionVenlafaxine treatment is associated with sustained increases in blood pressure in some patients.Among patients treated with 75 to 375 mg/day of Effexor XR in premarketing studies in patientswith major depressive disorder, 3% (19/705) experienced sustained hypertension [defined astreatment-emergent supine diastolic blood pressure (SDBP) ≥ 90 mm Hg and ≥ 10 mm Hg abovebaseline for 3 consecutive on-therapy visits]. Among patients treated with 37.5 to 225 mg/day ofEffexor XR in premarketing GAD studies, 0.5% (5/1011) experienced sustained hypertension.Among patients treated with 75 to 225 mg/day of Effexor XR in premarketing Social AnxietyDisorder studies, 1.4% (4/277) experienced sustained hypertension. Experience with theimmediate-release venlafaxine showed that sustained hypertension was dose-related, increasingfrom 3% to 7% at 100 to 300 mg/day to 13% at doses above 300 mg/day. An insufficient number

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of patients received mean doses of Effexor XR over 300 mg/day to fully evaluate the incidenceof sustained increases in blood pressure at these higher doses.

In placebo-controlled premarketing studies in patients with major depressive disorder withEffexor XR 75 to 225 mg/day, a final on-drug mean increase in supine diastolic blood pressure(SDBP) of 1.2 mm Hg was observed for Effexor XR-treated patients compared with a meandecrease of 0.2 mm Hg for placebo-treated patients. In placebo-controlled premarketing GADstudies with Effexor XR 37.5 to 225 mg/day, up to 8 weeks or up to 6 months, a final on-drugmean increase in SDBP of 0.3 mm Hg was observed for Effexor XR-treated patients comparedwith a mean decrease of 0.9 and 0.8 mm Hg, respectively, for placebo-treated patients. Inplacebo-controlled premarketing Social Anxiety Disorder studies with Effexor XR75 to 225 mg/day up to 12 weeks, a final on-drug mean increase in SDBP of 1.3 mm Hg wasobserved for Effexor XR-treated patients compared with a mean decrease of 1.3 mm Hg forplacebo-treated patients.

In premarketing major depressive disorder studies, 0.7% (5/705) of the Effexor XR-treatedpatients discontinued treatment because of elevated blood pressure. Among these patients, mostof the blood pressure increases were in a modest range (12 to 16 mm Hg, SDBP). Inpremarketing GAD studies up to 8 weeks and up to 6 months, 0.7% (10/1381) and1.3% (7/535) of the Effexor XR-treated patients, respectively, discontinued treatment because ofelevated blood pressure. Among these patients, most of the blood pressure increases were in amodest range (12 to 25 mm Hg, SDBP up to 8 weeks; 8 to 28 mm Hg up to 6 months). Inpremarketing Social Anxiety Disorder studies up to 12 weeks, 0.4% (1/277) of theEffexor XR-treated patients discontinued treatment because of elevated blood pressure. In thispatient, the blood pressure increase was modest (13 mm Hg, SDBP).

Sustained increases of SDBP could have adverse consequences. Therefore, it is recommendedthat patients receiving Effexor XR have regular monitoring of blood pressure. For patients whoexperience a sustained increase in blood pressure while receiving venlafaxine, either dosereduction or discontinuation should be considered.

PRECAUTIONSGeneralDiscontinuation of Treatment with Effexor XRDiscontinuation symptoms have been systematically evaluated in patients taking venlafaxine, toinclude prospective analyses of clinical trials in Generalized Anxiety Disorder and retrospectivesurveys of trials in major depressive disorder. Abrupt discontinuation or dose reduction ofvenlafaxine at various doses has been found to be associated with the appearance of newsymptoms, the frequency of which increased with increased dose level and with longer durationof treatment. Reported symptoms include agitation, anorexia, anxiety, confusion, coordinationimpaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches,hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances (includingshock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting.

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During marketing of Effexor XR, other SNRIs (Serotonin and Norepinephrine ReuptakeInhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneousreports of adverse events occurring upon discontinuation of these drugs, particularly whenabrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensorydisturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache,lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events aregenerally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment withEffexor XR. A gradual reduction in the dose rather than abrupt cessation is recommendedwhenever possible. If intolerable symptoms occur following a decrease in the dose or upondiscontinuation of treatment, then resuming the previously prescribed dose may be considered.Subsequently, the physician may continue decreasing the dose but at a more gradual rate (seeDOSAGE AND ADMINISTRATION).

Insomnia and NervousnessTreatment-emergent insomnia and nervousness were more commonly reported for patientstreated with Effexor XR (venlafaxine hydrochloride) extended-release capsules than withplacebo in pooled analyses of short-term major depressive disorder, GAD, and Social AnxietyDisorder studies, as shown in Table 1.

Table 1Incidence of Insomnia and Nervousness in Placebo-Controlled Major Depressive Disorder,

GAD, and Social Anxiety Disorder TrialsMajor Depressive

DisorderGAD Social Anxiety

Disorder

SymptomEffexor XR

n = 357Placebon = 285

Effexor XRn = 1381

Placebon = 555

Effexor XRn = 277

Placebon = 274

Insomnia 17% 11% 15% 10% 23% 7%Nervousness 10% 5% 6% 4% 11% 3%

Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated withEffexor XR in major depressive disorder studies.

In GAD trials, insomnia and nervousness led to drug discontinuation in 3% and 2%, respectively,of the patients treated with Effexor XR up to 8 weeks and 2% and 0.7%, respectively, of thepatients treated with Effexor XR up to 6 months.

In Social Anxiety Disorder trials, insomnia and nervousness led to drug discontinuation in3% and 0%, respectively, of the patients treated with Effexor XR up to 12 weeks.

Changes in Appetite and WeightTreatment-emergent anorexia was more commonly reported for Effexor XR treated (8%) thanplacebo treated patients (4%) in the pool of short-term studies in major depressive disorder.Significant weight loss, especially in underweight depressed patients, may be an undesirableeffect of Effexor XR treatment. A loss of 5% or more of body weight occurred in 7% ofEffexor XR-treated and 2% of placebo-treated patients in placebo-controlled major depressive

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disorder trials. Discontinuation rates for anorexia and weight loss associated with Effexor XRwere low (1.0% and 0.1%, respectively, of Effexor XR treated patients in major depressivedisorder studies).

In the pool of GAD studies, treatment emergent anorexia was reported in 8% and 2% of patientsreceiving Effexor XR and placebo up to 8 weeks, respectively. A loss of 7% or more of bodyweight occurred in 3% of the Effexor XR-treated and 1% of the placebo-treated patients up to6 months in these trials. Discontinuation rates for anorexia and weight loss were low for patientsreceiving Effexor XR up to 8 weeks (0.9% and 0.3%, respectively).

In the pool of Social Anxiety Disorder studies, treatment emergent anorexia was reported in20% and 2% of patients receiving Effexor XR and placebo up to 12 weeks, respectively. A lossof 7% or more of body weight occurred in 3% of the Effexor XR-treated and 0.4% of theplacebo-treated patients up to 12 weeks in these trials. Discontinuation rates for anorexia andweight loss were low for patients receiving Effexor XR up to 12 weeks (0.4% and 0.0%,respectively).

The safety and efficacy of venlafaxine therapy in combination with weight loss agents, includingphentermine, have not been established. Co-administration of Effexor XR and weight loss agentsis not recommended. Effexor XR is not indicated for weight loss alone or in combination withother products.

Activation of Mania/HypomaniaDuring premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% ofEffexor XR-treated patients and 0.0% placebo patients. In premarketing GAD studies, 0.0% ofEffexor XR-treated patients and 0.2% of placebo-treated patients experienced mania orhypomania. In premarketing Social Anxiety Disorder studies, no Effexor XR-treated patients andno placebo-treated patients experienced mania or hypomania. In all premarketing majordepressive disorder trials with Effexor, mania or hypomania occurred in 0.5% ofvenlafaxine-treated patients compared with 0% of placebo patients. Mania/hypomania has alsobeen reported in a small proportion of patients with mood disorders who were treated with othermarketed drugs to treat major depressive disorder. As with all drugs effective in the treatment ofmajor depressive disorder, Effexor XR should be used cautiously in patients with a history ofmania.

HyponatremiaHyponatremia and/or the syndrome of inappropriate antidiuretic hormone secretion (SIADH)may occur with venlafaxine. This should be taken into consideration in patients who are, forexample, volume-depleted, elderly, or taking diuretics.

MydriasisMydriasis has been reported in association with venlafaxine; therefore patients with raisedintraocular pressure or those at risk of acute narrow-angle glaucoma should be monitored.

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SeizuresDuring premarketing experience, no seizures occurred among 705 Effexor XR-treated patients inthe major depressive disorder studies, among 1381 Effexor XR-treated patients in GAD studies,or among 277 Effexor XR-treated patients in Social Anxiety Disorder studies. In allpremarketing major depressive disorder trials with Effexor, seizures were reported at variousdoses in 0.3% (8/3082) of venlafaxine-treated patients. Effexor XR, like many antidepressants,should be used cautiously in patients with a history of seizures and should be discontinued in anypatient who develops seizures.

Abnormal BleedingThere have been reports of abnormal bleeding (most commonly ecchymosis) associated withvenlafaxine treatment. While a causal relationship to venlafaxine is unclear, impaired plateletaggregation may result from platelet serotonin depletion and contribute to such occurrences.

Serum Cholesterol ElevationClinically relevant increases in serum cholesterol were recorded in 5.3% of venlafaxine-treatedpatients and 0.0% of placebo-treated patients treated for at least 3 months in placebo-controlledtrials (see ADVERSE REACTIONS-Laboratory Changes). Measurement of serum cholesterollevels should be considered during long-term treatment.

Use in Patients With Concomitant IllnessPremarketing experience with venlafaxine in patients with concomitant systemic illness islimited. Caution is advised in administering Effexor XR to patients with diseases or conditionsthat could affect hemodynamic responses or metabolism.

Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recenthistory of myocardial infarction or unstable heart disease. Patients with these diagnoses weresystematically excluded from many clinical studies during venlafaxine's premarketing testing.The electrocardiograms were analyzed for 275 patients who received Effexor XR and220 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials inmajor depressive disorder, for 610 patients who received Effexor XR and 298 patients whoreceived placebo in 8-week double-blind, placebo-controlled trials in GAD, and for 195 patientswho received Effexor XR and 228 patients who received placebo in 12-week double-blind,placebo-controlled trials in Social Anxiety Disorder. The mean change from baseline incorrected QT interval (QTc) for Effexor XR-treated patients in major depressive disorder studieswas increased relative to that for placebo-treated patients (increase of 4.7 msec for Effexor XRand decrease of 1.9 msec for placebo). The mean change from baseline in corrected QT interval(QTc) for Effexor XR-treated patients in the GAD studies did not differ significantly from thatwith placebo. The mean change from baseline in QTc for Effexor XR-treated patients in theSocial Anxiety Disorder studies was increased relative to that for placebo-treated patients(increase of 2.8 msec for Effexor XR and decrease of 2.0 msec for placebo).

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In these same trials, the mean change from baseline in heart rate for Effexor XR-treated patientsin the major depressive disorder studies was significantly higher than that for placebo (a meanincrease of 4 beats per minute for Effexor XR and 1 beat per minute for placebo). The meanchange from baseline in heart rate for Effexor XR-treated patients in the GAD studies wassignificantly higher than that for placebo (a mean increase of 3 beats per minute for Effexor XRand no change for placebo). The mean change from baseline in heart rate for Effexor XR-treatedpatients in the Social Anxiety Disorder studies was significantly higher than that for placebo (amean increase of 5 beats per minute for Effexor XR and no change for placebo).

In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dosegreater than 300 mg/day, Effexor-treated patients had a mean increase in heart rate of 8.5 beatsper minute compared with 1.7 beats per minute in the placebo group.

As increases in heart rate were observed, caution should be exercised in patients whoseunderlying medical conditions might be compromised by increases in heart rate (eg, patients withhyperthyroidism, heart failure, or recent myocardial infarction), particularly when using doses ofEffexor above 200 mg/day.

Evaluation of the electrocardiograms for 769 patients who received immediate release Effexor in4- to 6-week double-blind, placebo-controlled trials showed that the incidence of trial-emergentconduction abnormalities did not differ from that with placebo.

In patients with renal impairment (GFR = 10 to 70 mL/min) or cirrhosis of the liver, theclearances of venlafaxine and its active metabolites were decreased, thus prolonging theelimination half-lives of these substances. A lower dose may be necessary (see DOSAGE ANDADMINISTRATION). Effexor XR, like all drugs effective in the treatment of major depressivedisorder, should be used with caution in such patients.

Information for PatientsPhysicians are advised to discuss the following issues with patients for whom they prescribeEffexor XR (venlafaxine hydrochloride) extended-release capsules:

Patients and their families should be encouraged to be alert to the emergence of anxiety,agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania,worsening of depression, and suicidal ideation, especially early during antidepressant treatment.Such symptoms should be reported to the patient’s physician, especially if they are severe, abruptin onset, or were not part of the patient’s presenting symptoms.

Interference with Cognitive and Motor PerformanceClinical studies were performed to examine the effects of venlafaxine on behavioral performanceof healthy individuals. The results revealed no clinically significant impairment of psychomotor,cognitive, or complex behavior performance. However, since any psychoactive drug may impairjudgment, thinking, or motor skills, patients should be cautioned about operating hazardousmachinery, including automobiles, until they are reasonably certain that venlafaxine therapy doesnot adversely affect their ability to engage in such activities.

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Concomitant MedicationPatients should be advised to inform their physicians if they are taking, or plan to take, anyprescription or over-the-counter drugs, including herbal preparations, since there is a potentialfor interactions.

AlcoholAlthough venlafaxine has not been shown to increase the impairment of mental and motor skillscaused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine.

Allergic ReactionsPatients should be advised to notify their physician if they develop a rash, hives, or a relatedallergic phenomenon.

PregnancyPatients should be advised to notify their physician if they become pregnant or intend to becomepregnant during therapy.

NursingPatients should be advised to notify their physician if they are breast-feeding an infant.

Laboratory TestsThere are no specific laboratory tests recommended.

Drug InteractionsAs with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

AlcoholA single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine orO-desmethylvenlafaxine (ODV) when venlafaxine was administered at 150 mg/day in 15 healthymale subjects. Additionally, administration of venlafaxine in a stable regimen did not exaggeratethe psychomotor and psychometric effects induced by ethanol in these same subjects when theywere not receiving venlafaxine.

CimetidineConcomitant administration of cimetidine and venlafaxine in a steady-state study for both drugsresulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oralclearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximumconcentration (Cmax) of the drug were increased by about 60%. However, coadministration ofcimetidine had no apparent effect on the pharmacokinetics of ODV, which is present in muchgreater quantity in the circulation than venlafaxine. The overall pharmacological activity ofvenlafaxine plus ODV is expected to increase only slightly, and no dosage adjustment should benecessary for most normal adults. However, for patients with pre-existing hypertension, and forelderly patients or patients with hepatic dysfunction, the interaction associated with theconcomitant use of venlafaxine and cimetidine is not known and potentially could be morepronounced. Therefore, caution is advised with such patients.

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DiazepamUnder steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg doseof diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics ofdiazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor andpsychometric effects induced by diazepam.

HaloperidolVenlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjectsdecreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, whichresulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased88% when coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) wasunchanged. The mechanism explaining this finding is unknown.

LithiumThe steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affectedwhen a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. ODValso was unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see alsoCNS-Active Drugs, below).

Drugs Highly Bound to Plasma ProteinsVenlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor XR to apatient taking another drug that is highly protein bound should not cause increased freeconcentrations of the other drug.

Drugs that Inhibit Cytochrome P450 IsoenzymesCYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to itsactive metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the geneticpolymorphism seen in the metabolism of many antidepressants. Therefore, the potential existsfor a drug interaction between drugs that inhibit CYP2D6-mediated metabolism of venlafaxine,reducing the metabolism of venlafaxine to ODV, resulting in increased plasma concentrations ofvenlafaxine and decreased concentrations of the active metabolite. CYP2D6 inhibitors such asquinidine would be expected to do this, but the effect would be similar to what is seen in patientswho are genetically CYP2D6 poor metabolizers (see Metabolism and Excretion underCLINICAL PHARMACOLOGY). Therefore, no dosage adjustment is required whenvenlafaxine is coadministered with a CYP2D6 inhibitor.

The concomitant use of venlafaxine with drug treatment(s) that potentially inhibits both CYP2D6and CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied.

Therefore, caution is advised should a patient’s therapy include venlafaxine and any agent(s) thatproduce simultaneous inhibition of these two enzyme systems.

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Drugs Metabolized by Cytochrome P450 IsoenzymesCYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6.These findings have been confirmed in a clinical drug interaction study comparing the effect ofvenlafaxine with that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphanto dextrorphan.

Imipramine - Venlafaxine did not affect the pharmacokinetics of imipramine and2-OH-imipramine. However, desipramine AUC, Cmax, and Cmin increased by about 35% in thepresence of venlafaxine. The 2-OH-desipramine AUC’s increased by at least 2.5 fold (withvenlafaxine 37.5 mg q12h) and by 4.5 fold (with venlafaxine 75 mg q12h). Imipramine did notaffect the pharmacokinetics of venlafaxine and ODV. The clinical significance of elevated2-OH-desipramine levels is unknown.

Risperidone - Venlafaxine administered under steady-state conditions at 150 mg/day slightlyinhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oraldose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase inrisperidone AUC. However, venlafaxine coadministration did not significantly alter thepharmacokinetic profile of the total active moiety (risperidone plus 9-hydroxyrisperidone).

CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo byclinical drug interaction studies in which venlafaxine did not inhibit the metabolism of severalCYP3A4 substrates, including alprazolam, diazepam, and terfenadine.

Indinavir - In a study of 9 healthy volunteers, venlafaxine administered under steady-stateconditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose ofindinavir and a 36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics ofvenlafaxine and ODV. The clinical significance of this finding is unknown.

CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by aclinical drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, aCYP1A2 substrate.

CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouthevery 12 hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or theCYP2C9 mediated formation of 4-hydroxy-tolbutamide.

CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam, which is partiallymetabolized by CYP2C19 (see Diazepam above).

Monoamine Oxidase InhibitorsSee CONTRAINDICATIONS and WARNINGS.

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CNS-Active DrugsThe risk of using venlafaxine in combination with other CNS-active drugs has not beensystematically evaluated (except in the case of those CNS-active drugs noted above).Consequently, caution is advised if the concomitant administration of venlafaxine and such drugsis required. Based on the mechanism of action of venlafaxine and the potential for serotoninsyndrome, caution is advised when venlafaxine is co-administered with other drugs that mayaffect the serotonergic neurotransmitter systems, such as triptans, serotonin reuptake inhibitors(SRIs), or lithium.

Electroconvulsive TherapyThere are no clinical data establishing the benefit of electroconvulsive therapy combined withEffexor XR (venlafaxine hydrochloride) extended-release capsules treatment.

Postmarketing Spontaneous Drug Interaction ReportsSee ADVERSE REACTIONS, Postmarketing Reports.

Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisVenlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day,which was 1.7 times the maximum recommended human dose on a mg/m2 basis. Venlafaxinewas also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In ratsreceiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 1 times(male rats) and 6 times (female rats) the plasma concentrations of patients receiving themaximum recommended human dose. Plasma levels of the O-desmethyl metabolite were lowerin rats than in patients receiving the maximum recommended dose. Tumors were not increasedby venlafaxine treatment in mice or rats.

MutagenesisVenlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were notmutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamsterovary/HGPRT mammalian cell forward gene mutation assay. Venlafaxine was also notmutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sisterchromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivochromosomal aberration assay in rat bone marrow. ODV was not clastogenic in the in vitroChinese hamster ovary cell chromosomal aberration assay, but elicited a clastogenic response inthe in vivo chromosomal aberration assay in rat bone marrow.

Impairment of FertilityReproduction and fertility studies in rats showed no effects on male or female fertility at oraldoses of up to 2 times the maximum recommended human dose on a mg/m2 basis.

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PregnancyTeratogenic Effects - Pregnancy Category CVenlafaxine did not cause malformations in offspring of rats or rabbits given doses up to2.5 times (rat) or 4 times (rabbit) the maximum recommended human daily dose ona mg/m2 basis. However, in rats, there was a decrease in pup weight, an increase in stillbornpups, and an increase in pup deaths during the first 5 days of lactation, when dosing beganduring pregnancy and continued until weaning. The cause of these deaths is not known. Theseeffects occurred at 2.5 times (mg/m2) the maximum human daily dose. The no effect dose for ratpup mortality was 0.25 times the human dose on a mg/m2 basis. There are no adequate andwell-controlled studies in pregnant women. Because animal reproduction studies are not alwayspredictive of human response, this drug should be used during pregnancy only if clearly needed.

Non-teratogenic EffectsNeonates exposed to Effexor XR, other SNRIs (Serotonin and Norepinephrine ReuptakeInhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late in the third trimester havedeveloped complications requiring prolonged hospitalization, respiratory support, and tubefeeding. Such complications can arise immediately upon delivery. Reported clinical findingshave included respiratory distress, cyanosis, apnea, seizures, temperature instability, feedingdifficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness,irritability, and constant crying. These features are consistent with either a direct toxic effect ofSSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in somecases, the clinical picture is consistent with serotonin syndrome (see PRECAUTIONS-DrugInteractions-CNS-Active Drugs). When treating a pregnant woman with Effexor XR during thethird trimester, the physician should carefully consider the potential risks and benefits oftreatment (see DOSAGE AND ADMINISTRATION).

Labor and DeliveryThe effect of venlafaxine on labor and delivery in humans is unknown.

Nursing MothersVenlafaxine and ODV have been reported to be excreted in human milk. Because of the potentialfor serious adverse reactions in nursing infants from Effexor XR, a decision should be madewhether to discontinue nursing or to discontinue the drug, taking into account the importance ofthe drug to the mother.

Pediatric UseSafety and effectiveness in pediatric patients have not been established. (SeeWARNINGS-Clinical Worsening and Suicide Risk).

Geriatric UseApproximately 4% (14/357), 6% (77/1381), and 2% (6/277) of Effexor XR-treated patients inplacebo-controlled premarketing major depressive disorder, GAD, and Social Anxiety Disordertrials, respectively, were 65 years of age or over. Of 2,897 Effexor-treated patients inpremarketing phase major depressive disorder studies, 12% (357) were 65 years of age or over.No overall differences in effectiveness or safety were observed between geriatric patients andyounger patients, and other reported clinical experience generally has not identified differencesin response between the elderly and younger patients. However, greater sensitivity of some older

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individuals cannot be ruled out. As with other antidepressants, several cases of hyponatremia andsyndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported, usuallyin the elderly.

The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly (seeCLINICAL PHARMACOLOGY). No dose adjustment is recommended for the elderly on thebasis of age alone, although other clinical circumstances, some of which may be more commonin the elderly, such as renal or hepatic impairment, may warrant a dose reduction (see DOSAGEAND ADMINISTRATION).

ADVERSE REACTIONSThe information included in the Adverse Findings Observed in Short-Term,Placebo-Controlled Studies with Effexor XR subsection is based on data from a pool of three8- and 12-week controlled clinical trials in major depressive disorder (includes two U.S. trialsand one European trial), on data up to 8 weeks from a pool of five controlled clinical trials inGAD with Effexor XR , and on data up to 12 weeks from a pool of two controlled clinical trialsin Social Anxiety Disorder. Information on additional adverse events associated with Effexor XRin the entire development program for the formulation and with Effexor (the immediate releaseformulation of venlafaxine) is included in the Other Adverse Events Observed During thePremarketing Evaluation of Effexor and Effexor XR subsection (see also WARNINGS andPRECAUTIONS).

Adverse Findings Observed in Short-Term, Placebo-Controlled Studies withEffexor XRAdverse Events Associated with Discontinuation of TreatmentApproximately 11% of the 357 patients who received Effexor XR (venlafaxine hydrochloride)extended-release capsules in placebo-controlled clinical trials for major depressive disorderdiscontinued treatment due to an adverse experience, compared with 6% of the 285placebo-treated patients in those studies. Approximately 18% of the 1381 patients who receivedEffexor XR capsules in placebo-controlled clinical trials for GAD discontinued treatment due toan adverse experience, compared with 12% of the 555 placebo-treated patients in those studies.Approximately 17% of the 277 patients who received Effexor XR capsules in placebo-controlledclinical trials for Social Anxiety Disorder discontinued treatment due to an adverse experience,compared with 5% of the 274 placebo-treated patients in those studies. The most common eventsleading to discontinuation and considered to be drug-related (ie, leading to discontinuation in atleast 1% of the Effexor XR-treated patients at a rate at least twice that of placebo for eitherindication) are shown in Table 2.

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Table 2Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials1

Percentage of Patients Discontinuing Due to Adverse EventAdverse Event Major Depressive

Disorder Indication2GAD Indication3,4 Social Anxiety

Disorder IndicationEffexor XR

n = 357Placebon = 285

Effexor XRn = 1381

Placebon = 555

Effexor XRn = 277

Placebon = 274

Body as a WholeAsthenia -- -- 3% <1% 1% <1%Headache -- -- -- -- 2% <1%

Digestive SystemNausea 4% <1% 8% <1% 4% 0%Anorexia 1% <1% -- -- -- --Dry Mouth 1% 0% 2% <1% -- --Vomiting -- -- 1% <1% -- --

Nervous SystemDizziness 2% 1% -- -- 2% 0%Insomnia 1% <1% 3% <1% 3% <1%Somnolence 2% <1% 3% <1% 2% <1%Nervousness -- -- 2% <1% -- --Tremor -- -- 1% 0% -- --Anxiety -- -- -- -- 1% <1%

SkinSweating -- -- 2% <1% 1% 0%

Urogenital SystemImpotence5 -- -- -- -- 3% 0%

1 Two of the major depressive disorder studies were flexible dose and one was fixed dose. Fourof the GAD studies were fixed dose and one was flexible dose. Both of the Social AnxietyDisorder studies were flexible dose.2 In U.S. placebo-controlled trials for major depressive disorder, the following were alsocommon events leading to discontinuation and were considered to be drug-related forEffexor XR-treated patients (% Effexor XR [n = 192], % Placebo [n = 202]): hypertension(1%, <1%); diarrhea (1%, 0%); paresthesia (1%, 0%); tremor (1%, 0%); abnormal vision, mostlyblurred vision (1%, 0%); and abnormal, mostly delayed, ejaculation (1%, 0%).3 In two short-term U.S. placebo-controlled trials for GAD, the following were also commonevents leading to discontinuation and were considered to be drug-related for Effexor XR-treatedpatients (% Effexor XR [n = 476]), % Placebo [n = 201]: headache (4%, <1%); vasodilatation(1%, 0%); anorexia (2%, <1%); dizziness (4%, 1%); thinking abnormal (1%, 0%); and abnormalvision (1%, 0%).4 In long-term placebo-controlled trials for GAD, the following was also a common eventleading to discontinuation and was considered to be drug-related for Effexor XR-treated patients(% Effexor XR [n = 535], % Placebo [n = 257]): decreased libido (1%, 0%).5 Incidence is based on the number of men (Effexor XR = 158, placebo = 153).

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Adverse Events Occurring at an Incidence of 2% or More Among Effexor XR-TreatedPatientsTables 3, 4, and 5 enumerate the incidence, rounded to the nearest percent, oftreatment-emergent adverse events that occurred during acute therapy of major depressivedisorder (up to 12 weeks; dose range of 75 to 225 mg/day), of GAD (up to 8 weeks; dose rangeof 37.5 to 225 mg/day), and of Social Anxiety Disorder (up to 12 weeks; dose range of75 to 225 mg/day), respectively, in 2% or more of patients treated with Effexor XR (venlafaxinehydrochloride) where the incidence in patients treated with Effexor XR was greater than theincidence for the respective placebo-treated patients. The table shows the percentage of patientsin each group who had at least one episode of an event at some time during their treatment.Reported adverse events were classified using a standard COSTART-based Dictionaryterminology.

The prescriber should be aware that these figures cannot be used to predict the incidence of sideeffects in the course of usual medical practice where patient characteristics and other factorsdiffer from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot becompared with figures obtained from other clinical investigations involving different treatments,uses and investigators. The cited figures, however, do provide the prescribing physician withsome basis for estimating the relative contribution of drug and nondrug factors to the side effectincidence rate in the population studied.

Commonly Observed Adverse Events from Tables 3, 4, and 5:

Major Depressive DisorderNote in particular the following adverse events that occurred in at least 5% of the Effexor XRpatients and at a rate at least twice that of the placebo group for all placebo-controlled trials forthe major depressive disorder (Table 3): Abnormal ejaculation, gastrointestinal complaints(nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormaldreams), and sweating. In the two U.S. placebo-controlled trials, the following additional eventsoccurred in at least 5% of Effexor XR-treated patients (n = 192) and at a rate at least twice that ofthe placebo group: Abnormalities of sexual function (impotence in men, anorgasmia in women,and libido decreased), gastrointestinal complaints (constipation and flatulence), CNS complaints(insomnia, nervousness, and tremor), problems of special senses (abnormal vision),cardiovascular effects (hypertension and vasodilatation), and yawning.

Generalized Anxiety DisorderNote in particular the following adverse events that occurred in at least 5% of the Effexor XRpatients and at a rate at least twice that of the placebo group for all placebo-controlled trials forthe GAD indication (Table 4): Abnormalities of sexual function (abnormal ejaculation andimpotence), gastrointestinal complaints (nausea, dry mouth, anorexia, and constipation),problems of special senses (abnormal vision), and sweating.

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Social Anxiety DisorderNote in particular the following adverse events that occurred in at least 5% of the Effexor XRpatients and at a rate at least twice that of the placebo group for the 2 placebo-controlled trials forthe Social Anxiety Disorder indication (Table 5): Asthenia, gastrointestinal complaints (anorexia,dry mouth, nausea), CNS complaints (anxiety, insomnia, libido decreased, nervousness,somnolence, dizziness), abnormalities of sexual function (abnormal ejaculation, orgasmicdysfunction, impotence), yawn, sweating, and abnormal vision.

Table 3Treatment-Emergent Adverse Event Incidence in Short-Term Placebo-Controlled

Effexor XR Clinical Trials in Patients with Major Depressive Disorder1,2

% Reporting EventBody System

Preferred TermEffexor XR

(n = 357)Placebo(n = 285)

Body as a WholeAsthenia 8% 7%

Cardiovascular SystemVasodilatation3 4% 2%Hypertension 4% 1%

Digestive SystemNausea 31% 12%Constipation 8% 5%Anorexia 8% 4%Vomiting 4% 2%Flatulence 4% 3%

Metabolic/NutritionalWeight Loss 3% 0%

Nervous SystemDizziness 20% 9%Somnolence 17% 8%Insomnia 17% 11%Dry Mouth 12% 6%Nervousness 10% 5%Abnormal Dreams4 7% 2%Tremor 5% 2%Depression 3% <1%Paresthesia 3% 1%Libido Decreased 3% <1%Agitation 3% 1%

Respiratory SystemPharyngitis 7% 6%Yawn 3% 0%

SkinSweating 14% 3%

Special SensesAbnormal Vision5 4% <1%

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Preferred TermEffexor XR

(n = 357)Placebo(n = 285)

Urogenital SystemAbnormal Ejaculation 16% <1%(male)6,7

Impotence7 4% <1%Anorgasmia (female)8,9 3% <1%

1 Incidence, rounded to the nearest %, for events reported by at least 2% of patients treated withEffexor XR, except the following events which had an incidence equal to or less than placebo:abdominal pain, accidental injury, anxiety, back pain, bronchitis, diarrhea, dysmenorrhea,dyspepsia, flu syndrome, headache, infection, pain, palpitation, rhinitis, and sinusitis.2 <1% indicates an incidence greater than zero but less than 1%.3 Mostly “hot flashes.”4 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.”5 Mostly “blurred vision” and “difficulty focusing eyes.”6 Mostly “delayed ejaculation.”7 Incidence is based on the number of male patients.8 Mostly “delayed orgasm” or “anorgasmia.”9 Incidence is based on the number of female patients.


Effexor XR Clinical Trials in GAD Patients1,2


Preferred TermEffexor XR(n = 1381)

Placebo(n = 555)

Body as a WholeAsthenia 12% 8%

Cardiovascular SystemVasodilatation3 4% 2%

Digestive SystemNausea 35% 12%Constipation 10% 4%Anorexia 8% 2%Vomiting 5% 3%

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Preferred TermEffexor XR(n = 1381)

Placebo(n = 555)

Nervous SystemDizziness 16% 11%Dry Mouth 16% 6%Insomnia 15% 10%Somnolence 14% 8%Nervousness 6% 4%Libido Decreased 4% 2%Tremor 4% <1%Abnormal Dreams4 3% 2%Hypertonia 3% 2%Paresthesia 2% 1%

Respiratory SystemYawn 3% <1%

SkinSweating 10% 3%

Special SensesAbnormal Vision5 5% <1%

Urogenital SystemAbnormal Ejaculation6,7 11% <1%Impotence7 5% <1%Orgasmic Dysfunction (female)8,9 2% 0%

1 Adverse events for which the Effexor XR reporting rate was less than or equal to the placeborate are not included. These events are: abdominal pain, accidental injury, anxiety, back pain,diarrhea, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, pain, palpitation,pharyngitis, rhinitis, tinnitus, and urinary frequency.2 <1% means greater than zero but less than 1%.3 Mostly “hot flashes.”4 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.”5 Mostly “blurred vision” and “difficulty focusing eyes.”6 Includes “delayed ejaculation” and “anorgasmia.”7 Percentage based on the number of males (Effexor XR = 525, placebo = 220).8 Includes “delayed orgasm,” “abnormal orgasm,” and “anorgasmia.”9 Percentage based on the number of females (Effexor XR = 856, placebo = 335).

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Effexor XR Clinical Trials in Social Anxiety Disorder Patients1,2

% Reporting EventBody System Effexor XR Placebo

Preferred Term (n = 277) (n = 274)Body as a Whole

Headache 34% 33%Asthenia 17% 8%Flu Syndrome 6% 5%Accidental Injury 5% 3%Abdominal Pain 4% 3%

Cardiovascular SystemHypertension 5% 4%Vasodilatation3 3% 1%Palpitation 3% 1%

Digestive SystemNausea 29% 9%Anorexia4 20% 1%Constipation 8% 4%Diarrhea 6% 5%Vomiting 3% 2%Eructation 2% 0%

Metabolic/NutritionalWeight Loss 4% 0%

Nervous SystemInsomnia 23% 7%Dry Mouth 17% 4%Dizziness 16% 8%Somnolence 16% 8%Nervousness 11% 3%Libido Decreased 9% <1%Anxiety 5% 3%Agitation 4% 1%Tremor 4% <1%Abnormal Dreams5 4% <1%Paresthesia 3% <1%Twitching 2% 0%

Respiratory SystemYawn 5% <1%Sinusitis 2% 1%

SkinSweating 13% 2%

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% Reporting EventBody System Effexor XR Placebo

Preferred Term (n = 277) (n = 274)Special Senses

Abnormal Vision6 6% 3%

Urogenital SystemAbnormal Ejaculation7,8 16% 1%Impotence8 10% 1%Orgasmic Dysfunction9,10 8% 0%

1 Adverse events for which the Effexor XR reporting rate was less than or equal to the placeborate are not included. These events are: back pain, depression, dysmenorrhea, dyspepsia,infection, myalgia, pain, pharyngitis, rash, rhinitis, and upper respiratory infection.2 <1% means greater than zero but less than 1%.3 Mostly “hot flashes.”4 Mostly “decreased appetite” and “loss of appetite.”5 Mostly “vivid dreams,” “nightmares,” and “increased dreaming.”6 Mostly “blurred vision.”7 Includes “delayed ejaculation” and “anorgasmia.”8 Percentage based on the number of males (Effexor XR = 158, placebo = 153).9 Includes “abnormal orgasm” and “anorgasmia.”10 Percentage based on the number of females (Effexor XR = 119, placebo = 121).

Vital Sign ChangesEffexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeksin premarketing placebo-controlled major depressive disorder trials was associated with a meanfinal on-therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beatper minute for placebo. Effexor XR treatment for up to 8 weeks in premarketingplacebo-controlled GAD trials was associated with a mean final on-therapy increase in pulse rateof approximately 2 beats per minute, compared with less than 1 beat per minute for placebo.Effexor XR treatment for up to 12 weeks in premarketing placebo-controlled Social AnxietyDisorder trials was associated with a mean final on-therapy increase in pulse rate ofapproximately 4 beats per minute, compared with an increase of 1 beat per minute for placebo.(See the Sustained Hypertension section of WARNINGS for effects on blood pressure.)

In a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dosegreater than 300 mg/day, the mean pulse was increased by about 2 beats per minute comparedwith a decrease of about 1 beat per minute for placebo.

Laboratory ChangesEffexor XR (venlafaxine hydrochloride) extended-release capsules treatment for up to 12 weeksin premarketing placebo-controlled trials for major depressive disorder was associated with amean final on-therapy increase in serum cholesterol concentration of approximately 1.5 mg/dLcompared with a mean final decrease of 7.4 mg/dL for placebo. Effexor XR treatment for up to8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated withmean final on-therapy increases in serum cholesterol concentration of approximately 1.0 mg/dLand 2.3 mg/dL, respectively while placebo subjects experienced mean final decreases of

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4.9 mg/dL and 7.7 mg/dL, respectively. Effexor XR treatment for up to 12 weeks inpremarketing placebo-controlled Social Anxiety Disorder trials was associated with mean finalon-therapy increases in serum cholesterol concentration of approximately 11.4 mg/dL comparedwith a mean final decrease of 2.2 mg/dL for placebo.

Patients treated with Effexor tablets (the immediate-release form of venlafaxine) for at least3 months in placebo-controlled 12-month extension trials had a mean final on-therapy increase intotal cholesterol of 9.1 mg/dL compared with a decrease of 7.1 mg/dL among placebo-treatedpatients. This increase was duration dependent over the study period and tended to be greaterwith higher doses. Clinically relevant increases in serum cholesterol, defined as 1) a finalon-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to a value ≥261 mg/dL,or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL from baseline and to avalue ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and 0.0% ofplacebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation).

ECG ChangesIn a flexible-dose study, with Effexor doses in the range of 200 to 375 mg/day and mean dosegreater than 300 mg/day, the mean change in heart rate was 8.5 beats per minute compared with1.7 beats per minute for placebo.

(See the Use in Patients with Concomitant Illness section of PRECAUTIONS).

Other Adverse Events Observed During the Premarketing Evaluation of Effexorand Effexor XRDuring its premarketing assessment, multiple doses of Effexor XR were administered to705 patients in Phase 3 major depressive disorder studies and Effexor was administered to96 patients. During its premarketing assessment, multiple doses of Effexor XR were alsoadministered to 1381 patients in Phase 3 GAD studies and 277 patients in Phase 3 Social AnxietyDisorder studies. In addition, in premarketing assessment of Effexor, multiple doses wereadministered to 2897 patients in Phase 2 to Phase 3 studies for major depressive disorder. Theconditions and duration of exposure to venlafaxine in both development programs varied greatly,and included (in overlapping categories) open and double-blind studies, uncontrolled andcontrolled studies, inpatient (Effexor only) and outpatient studies, fixed-dose, and titrationstudies. Untoward events associated with this exposure were recorded by clinical investigatorsusing terminology of their own choosing. Consequently, it is not possible to provide ameaningful estimate of the proportion of individuals experiencing adverse events without firstgrouping similar types of untoward events into a smaller number of standardized eventcategories.

In the tabulations that follow, reported adverse events were classified using a standardCOSTART-based Dictionary terminology. The frequencies presented, therefore, represent theproportion of the 5356 patients exposed to multiple doses of either formulation of venlafaxinewho experienced an event of the type cited on at least one occasion while receiving venlafaxine.All reported events are included except those already listed in Tables 3, 4, and 5 and those eventsfor which a drug cause was remote. If the COSTART term for an event was so general as to beuninformative, it was replaced with a more informative term. It is important to emphasize that,

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although the events reported occurred during treatment with venlafaxine, they were notnecessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency usingthe following definitions: frequent adverse events are defined as those occurring on one or moreoccasions in at least 1/100 patients; infrequent adverse events are those occurring in1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Body as a whole - Frequent: chest pain substernal, chills, fever, neck pain; Infrequent: faceedema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivityreaction, suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma,cellulitis.

Cardiovascular system - Frequent: migraine, postural hypotension, tachycardia;Infrequent: angina pectoris, arrhythmia, extrasystoles, hypotension, peripheral vascular disorder(mainly cold feet and/or cold hands), syncope, thrombophlebitis; Rare: aortic aneurysm,arteritis, first-degree atrioventricular block, bigeminy, bradycardia, bundle branch block,capillary fragility, cerebral ischemia, coronary artery disease, congestive heart failure, heartarrest, cardiovascular disorder (mitral valve and circulatory disturbance), mucocutaneoushemorrhage, myocardial infarct, pallor.

Digestive system - Frequent: increased appetite; Infrequent: bruxism, colitis, dysphagia,tongue edema, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis,rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration;Rare: cheilitis, cholecystitis, cholelithiasis, esophageal spasms, duodenitis, hematemesis,gastrointestinal hemorrhage, gum hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction,parotitis, periodontitis, proctitis, increased salivation, soft stools, tongue discoloration.

Endocrine system - Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis.

Hemic and lymphatic system - Frequent: ecchymosis; Infrequent: anemia, leukocytosis,leukopenia, lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleedingtime increased, cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura.

Metabolic and nutritional - Frequent: edema, weight gain; Infrequent: alkaline phosphataseincreased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, SGOTincreased, SGPT increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN increased,creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal, hemochromatosis,hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia, hypocholesteremia,hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia.

Musculoskeletal system - Frequent: arthralgia; Infrequent: arthritis, arthrosis, bone pain, bonespurs, bursitis, leg cramps, myasthenia, tenosynovitis; Rare: pathological fracture, myopathy,osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture.

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Nervous system - Frequent: amnesia, confusion, depersonalization, hypesthesia, thinkingabnormal, trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral paresthesia, CNSstimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia,hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia, neuropathy,psychosis, seizure, abnormal speech, stupor; Rare: akinesia, alcohol abuse, aphasia,bradykinesia, buccoglossal syndrome, cerebrovascular accident, feeling drunk, loss ofconsciousness, delusions, dementia, dystonia, facial paralysis, abnormal gait, Guillain-BarreSyndrome, hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, nystagmus,paranoid reaction, paresis, psychotic depression, reflexes decreased, reflexes increased, suicidalideation, torticollis.

Respiratory system - Frequent: cough increased, dyspnea; Infrequent: asthma, chestcongestion, epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration;Rare: atelectasis, hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonaryembolus, sleep apnea.

Skin and appendages - Frequent: pruritus; Infrequent: acne, alopecia, brittle nails, contactdermatitis, dry skin, eczema, skin hypertrophy, maculopapular rash, psoriasis, urticaria;Rare: erythema nodosum, exfoliative dermatitis, lichenoid dermatitis, hair discoloration, skindiscoloration, furunculosis, hirsutism, leukoderma, petechial rash, pustular rash, vesiculobullousrash, seborrhea, skin atrophy, skin striae.

Special senses - Frequent: abnormality of accommodation, mydriasis, taste perversion;Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, hyperacusis,otitis media, parosmia, photophobia, taste loss, visual field defect; Rare: blepharitis,chromatopsia, conjunctival edema, deafness, exophthalmos, glaucoma, retinal hemorrhage,subconjunctival hemorrhage, keratitis, labyrinthitis, miosis, papilledema, decreased pupillaryreflex, otitis externa, scleritis, uveitis.

Urogenital system - Frequent: metrorrhagia,* prostatic disorder (prostatitis and enlargedprostate),* urination impaired, vaginitis*; Infrequent: albuminuria, amenorrhea,* cystitis,dysuria, hematuria, leukorrhea,* menorrhagia,* nocturia, bladder pain, breast pain, polyuria,pyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage*;Rare: abortion,* anuria, breast discharge, breast engorgement, balanitis,* breast enlargement,endometriosis,* female lactation,* fibrocystic breast, calcium crystalluria, cervicitis,* orchitis,*ovarian cyst,* prolonged erection,* gynecomastia (male),* hypomenorrhea,* kidney calculus,kidney pain, kidney function abnormal, mastitis, menopause,* pyelonephritis, oliguria,salpingitis,* urolithiasis, uterine hemorrhage,* uterine spasm,* vaginal dryness.*

*Based on the number of men and women as appropriate.

Postmarketing ReportsVoluntary reports of other adverse events temporally associated with the use of venlafaxine thathave been received since market introduction and that may have no causal relationship with theuse of venlafaxine include the following: agranulocytosis, anaphylaxis, aplastic anemia,catatonia, congenital anomalies, CPK increased, deep vein thrombophlebitis, delirium, EKGabnormalities such as QT prolongation; cardiac arrhythmias including atrial fibrillation,

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supraventricular tachycardia, ventricular extrasystoles, and rare reports of ventricular fibrillationand ventricular tachycardia, including torsade de pointes; epidermal necrosis/Stevens-JohnsonSyndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia and tardivedyskinesia), hemorrhage (including eye and gastrointestinal bleeding), hepatic events (includingGGT elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, orfailure; and fatty liver), involuntary movements, LDH increased, neuroleptic malignantsyndrome-like events (including a case of a 10-year-old who may have been takingmethylphenidate, was treated and recovered), neutropenia, night sweats, pancreatitis,pancytopenia, panic, prolactin increased, pulmonary eosinophilia, renal failure, rhabdomyolysis,serotonin syndrome, shock-like electrical sensations or tinnitus (in some cases, subsequent to thediscontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretichormone secretion (usually in the elderly).

There have been reports of elevated clozapine levels that were temporally associated withadverse events, including seizures, following the addition of venlafaxine. There have beenreports of increases in prothrombin time, partial thromboplastin time, or INR when venlafaxinewas given to patients receiving warfarin therapy.

DRUG ABUSE AND DEPENDENCEControlled Substance ClassEffexor XR (venlafaxine hydrochloride) extended-release capsules is not a controlled substance.

Physical and Psychological DependenceIn vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine,phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors.

Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primatedrug discrimination studies, venlafaxine showed no significant stimulant or depressant abuseliability.

Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGEAND ADMINISTRATION).

While venlafaxine has not been systematically studied in clinical trials for its potential for abuse,there was no indication of drug-seeking behavior in the clinical trials. However, it is not possibleto predict on the basis of premarketing experience the extent to which a CNS active drug will bemisused, diverted, and/or abused once marketed. Consequently, physicians should carefullyevaluate patients for history of drug abuse and follow such patients closely, observing them forsigns of misuse or abuse of venlafaxine (eg, development of tolerance, incrementation of dose,drug-seeking behavior).

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OVERDOSAGEHuman ExperienceAmong the patients included in the premarketing evaluation of Effexor XR, there were 2 reportsof acute overdosage with Effexor XR in major depressive disorder trials, either alone or incombination with other drugs. One patient took a combination of 6 g of Effexor XR and 2.5 mgof lorazepam. This patient was hospitalized, treated symptomatically, and recovered without anyuntoward effects. The other patient took 2.85 g of Effexor XR. This patient reported paresthesiaof all four limbs but recovered without sequelae.

There were 2 reports of acute overdose with Effexor XR in GAD trials. One patient took acombination of 0.75 g of Effexor XR and 200 mg of paroxetine and 50 mg of zolpidem. Thispatient was described as being alert, able to communicate, and a little sleepy. This patient washospitalized, treated with activated charcoal, and recovered without any untoward effects. Theother patient took 1.2 g of Effexor XR. This patient recovered and no other specific problemswere found. The patient had moderate dizziness, nausea, numb hands and feet, and hot-coldspells 5 days after the overdose. These symptoms resolved over the next week.

There were no reports of acute overdose with Effexor XR in Social Anxiety Disorder trials.

Among the patients included in the premarketing evaluation with Effexor, there were 14 reportsof acute overdose with venlafaxine, either alone or in combination with other drugs and/oralcohol. The majority of the reports involved ingestion in which the total dose of venlafaxinetaken was estimated to be no more than several-fold higher than the usual therapeutic dose. The3 patients who took the highest doses were estimated to have ingested approximately 6.75 g,2.75 g, and 2.5 g. The resultant peak plasma levels of venlafaxine for the latter 2 patients were6.24 and 2.35 µg/mL, respectively, and the peak plasma levels of O-desmethylvenlafaxine were3.37 and 1.30 µg/mL, respectively. Plasma venlafaxine levels were not obtained for the patientwho ingested 6.75 g of venlafaxine. All 14 patients recovered without sequelae. Most patientsreported no symptoms. Among the remaining patients, somnolence was the most commonlyreported symptom. The patient who ingested 2.75 g of venlafaxine was observed to have2 generalized convulsions and a prolongation of QTc to 500 msec, compared with 405 msec atbaseline. Mild sinus tachycardia was reported in 2 of the other patients.

In postmarketing experience, overdose with venlafaxine has occurred predominantly incombination with alcohol and/or other drugs. Electrocardiogram changes (eg, prolongation ofQT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia,bradycardia, hypotension, altered level of consciousness (ranging from somnolence to coma),rhabdomyolysis, seizures, vertigo, and death have been reported.

Management of OverdosageTreatment should consist of those general measures employed in the management of overdosagewith any antidepressant.

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Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs.General supportive and symptomatic measures are also recommended. Induction of emesis is notrecommended. Gastric lavage with a large bore orogastric tube with appropriate airwayprotection, if needed, may be indicated if performed soon after ingestion or in symptomaticpatients.

Activated charcoal should be administered. Due to the large volume of distribution of this drug,forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.No specific antidotes for venlafaxine are known.

In managing overdosage, consider the possibility of multiple drug involvement. The physicianshould consider contacting a poison control center for additional information on the treatment ofany overdose. Telephone numbers for certified poison control centers are listed in thePhysicians’ Desk Reference (PDR).

DOSAGE AND ADMINISTRATIONEffexor XR should be administered in a single dose with food either in the morning or in theevening at approximately the same time each day. Each capsule should be swallowed whole withfluid and not divided, crushed, chewed, or placed in water, or it may be administered by carefullyopening the capsule and sprinkling the entire contents on a spoonful of applesauce. Thisdrug/food mixture should be swallowed immediately without chewing and followed with a glassof water to ensure complete swallowing of the pellets.

Initial TreatmentMajor Depressive DisorderFor most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered ina single dose. In the clinical trials establishing the efficacy of Effexor XR in moderatelydepressed outpatients, the initial dose of venlafaxine was 75 mg/day. For some patients, it maybe desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients to adjust to themedication before increasing to 75 mg/day. While the relationship between dose andantidepressant response for Effexor XR has not been adequately explored, patients notresponding to the initial 75 mg/day dose may benefit from dose increases to a maximum ofapproximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, asneeded, and should be made at intervals of not less than 4 days, since steady state plasma levelsof venlafaxine and its major metabolites are achieved in most patients by day 4. In the clinicaltrials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; theaverage doses were about 140 to 180 mg/day (see Clinical Trials under CLINICALPHARMACOLOGY).

It should be noted that, while the maximum recommended dose for moderately depressedoutpatients is also 225 mg/day for Effexor (the immediate release form of venlafaxine), moreseverely depressed inpatients in one study of the development program for that productresponded to a mean dose of 350 mg/day (range of 150 to 375 mg/day). Whether or not higherdoses of Effexor XR are needed for more severely depressed patients is unknown; however, theexperience with Effexor XR doses higher than 225 mg/day is very limited. (SeePRECAUTIONS-General-Use in Patients with Concomitant Illness.)

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Generalized Anxiety DisorderFor most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered ina single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients withGeneralized Anxiety Disorder (GAD), the initial dose of venlafaxine was 75 mg/day. For somepatients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, to allow new patients toadjust to the medication before increasing to 75 mg/day. Although a dose-response relationshipfor effectiveness in GAD was not clearly established in fixed-dose studies, certain patients notresponding to the initial 75 mg/day dose may benefit from dose increases to a maximum ofapproximately 225 mg/day. Dose increases should be in increments of up to 75 mg/day, asneeded, and should be made at intervals of not less than 4 days. (See the Use in Patients withConcomitant Illness section of PRECAUTIONS.)

Social Anxiety Disorder (Social Phobia)For most patients, the recommended starting dose for Effexor XR is 75 mg/day, administered ina single dose. In clinical trials establishing the efficacy of Effexor XR in outpatients with SocialAnxiety Disorder, the initial dose of Effexor XR was 75 mg/day and the maximum dose was225 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days, toallow new patients to adjust to the medication before increasing to 75 mg/day. Although adose-response relationship for effectiveness in patients with Social Anxiety Disorder was notclearly established in fixed-dose studies, certain patients not responding to the initial 75 mg/daydose may benefit from dose increases to a maximum of approximately 225 mg/day. Doseincreases should be in increments of up to 75 mg/day, as needed, and should be made at intervalsof not less than 4 days. (See the Use in Patients with Concomitant Illness section ofPRECAUTIONS).

Switching Patients from Effexor TabletsDepressed patients who are currently being treated at a therapeutic dose with Effexor may beswitched to Effexor XR at the nearest equivalent dose (mg/day), eg, 37.5 mg venlafaxinetwo-times-a-day to 75 mg Effexor XR once daily. However, individual dosage adjustments maybe necessary.

Special PopulationsTreatment of Pregnant Women During the Third TrimesterNeonates exposed to Effexor XR, other SNRIs, or SSRIs, late in the third trimester havedeveloped complications requiring prolonged hospitalization, respiratory support, and tubefeeding (see PRECAUTIONS). When treating pregnant women with Effexor XR during thethird trimester, the physician should carefully consider the potential risks and benefits oftreatment. The physician may consider tapering Effexor XR in the third trimester.

Patients with Hepatic ImpairmentGiven the decrease in clearance and increase in elimination half-life for both venlafaxine andODV that is observed in patients with hepatic cirrhosis compared with normal subjects (seeCLINICAL PHARMACOLOGY), it is recommended that the starting dose be reduced by50% in patients with moderate hepatic impairment. Because there was much individualvariability in clearance between patients with cirrhosis, individualization of dosage may bedesirable in some patients.

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Patients with Renal ImpairmentGiven the decrease in clearance for venlafaxine and the increase in elimination half-life for bothvenlafaxine and ODV that is observed in patients with renal impairment(GFR = 10 to 70 mL/min) compared with normal subjects (see CLINICALPHARMACOLOGY), it is recommended that the total daily dose be reduced by 25% to 50%.In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by50% and that the dose be withheld until the dialysis treatment is completed (4 hrs). Because therewas much individual variability in clearance between patients with renal impairment,individualization of dosage may be desirable in some patients.

Elderly PatientsNo dose adjustment is recommended for elderly patients solely on the basis of age. As with anydrug for the treatment of major depressive disorder, Generalized Anxiety Disorder, or SocialAnxiety Disorder, however, caution should be exercised in treating the elderly. Whenindividualizing the dosage, extra care should be taken when increasing the dose.

Maintenance TreatmentThere is no body of evidence available from controlled trials to indicate how long patients withmajor depressive disorder, Generalized Anxiety Disorder, or Social Anxiety Disorder should betreated with Effexor XR.

It is generally agreed that acute episodes of major depressive disorder require several months orlonger of sustained pharmacological therapy beyond response to the acute episode. In one study,in which patients responding during 8 weeks of acute treatment with Effexor XR were assignedrandomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during26 weeks of maintenance treatment as they had received during the acute stabilization phase,longer-term efficacy was demonstrated. A second longer-term study has demonstrated theefficacy of Effexor in maintaining a response in patients with recurrent major depressive disorderwho had responded and continued to be improved during an initial 26 weeks of treatment andwere then randomly assigned to placebo or Effexor for periods of up to 52 weeks on the samedose (100 to 200 mg/day, on a b.i.d. schedule) (see Clinical Trials under CLINICALPHARMACOLOGY). Based on these limited data, it is not known whether or not the dose ofEffexor/Effexor XR needed for maintenance treatment is identical to the dose needed to achievean initial response. Patients should be periodically reassessed to determine the need formaintenance treatment and the appropriate dose for such treatment.

In patients with Generalized Anxiety Disorder, Effexor XR has been shown to be effective in6-month clinical trials. The need for continuing medication in patients with GAD who improvewith Effexor XR treatment should be periodically reassessed.

In patients with Social Anxiety Disorder, there are no efficacy data beyond 12 weeks oftreatment with Effexor XR. The need for continuing medication in patients with Social AnxietyDisorder who improve with Effexor XR treatment should be periodically reassessed.

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Discontinuing Effexor XRSymptoms associated with discontinuation of Effexor XR, other SNRIs, and SSRIs, have beenreported (see PRECAUTIONS). Patients should be monitored for these symptoms whendiscontinuing treatment. A gradual reduction in the dose rather than abrupt cessation isrecommended whenever possible. If intolerable symptoms occur following a decrease in the doseor upon discontinuation of treatment, then resuming the previously prescribed dose may beconsidered. Subsequently, the physician may continue decreasing the dose but at a more gradualrate. In clinical trials with Effexor XR, tapering was achieved by reducing the daily dose by75 mg at 1 week intervals. Individualization of tapering may be necessary.

Switching Patients To or From a Monoamine Oxidase InhibitorAt least 14 days should elapse between discontinuation of an MAOI and initiation of therapywith Effexor XR. In addition, at least 7 days should be allowed after stopping Effexor XR beforestarting an MAOI (see CONTRAINDICATIONS and WARNINGS).

HOW SUPPLIEDEffexor XR (venlafaxine hydrochloride) extended-release capsules are available as follows:

37.5 mg, grey cap/peach body with and “Effexor XR” on the cap and “37.5” on the body.NDC 0008-0837-01, bottle of 100 capsules.NDC 0008-0837-03, carton of 10 Redipak blister strips of 10 capsules each.

Store at controlled room temperature, 20°C to 25°C (68°F to 77°F).

75 mg, peach cap and body with and “Effexor XR” on the cap and “75” on the body.NDC 0008-0833-01, bottle of 100 capsules.NDC 0008-0833-03, carton of 10 Redipak blister strips of 10 capsules each.


150 mg, dark orange cap and body with and “Effexor XR” on the cap and “150” on the body.NDC 0008-0836-01, bottle of 100 capsules.NDC 0008-0836-03, carton of 10 Redipak blister strips of 10 capsules each.


The appearance of these capsules is a trademark of Wyeth Pharmaceuticals.

Wyeth Pharmaceuticals Inc. W10404C009Philadelphia, PA 19101 ET01

Rev 04/04

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